Category Archives: Genetic medicine

When Dr. Ming Guo says that she wants to reverse the aging process, shes not outlining a fantastical quest for the Fountain of Youth. Shes looking for ways to defeat incurable diseases.

If we could pause, delay or even reverse aging, we would make a significant impact against numerous diseases, said Guo, professor of neurology, molecular and medical pharmacology at theDavid Geffen School of Medicine at UCLA.I want to create a higher quality of life over a healthy life span, rather than just prolonging life.

Her particular approach to her research is inspired by her compassion for her patients who have Alzheimers and Parkinsons diseases and other brain degenerative disorders, and from the discoveries she has made in her research lab.

The percentage of people with Alzheimer's doubles every five years after the age of 65, so Guo believes that intervening in the aging process could be the path to reducing the diseases massive impact. Slowing aging could also help combat a range of other diseases and conditions, including Parkinsons disease, heart disease, cancer and osteoporosis, as well as the increased vulnerability to infection that occurs with aging.

Since Guo joined the UCLA faculty two decades ago, her research focus has broadened to include multiple brain diseases and aging. In a landmark publication in 2006, Guo and her team examined two genes, PINK1 and PARKIN, that are mutated in some people with Parkinsons disease.

They discovered that the two genes work together to control the quality of cellular structures known as mitochondria by culling and recycling damaged ones. (Mitochondria provide energy to almost all cells in every complex organism on the planet, and they play a vital role in metabolism.)

The finding opened up a new investigation into the importance of PINK1 and PARKIN on mitochondrial health, and it helped establish Guos scientific legacy. Guo was honored, in 2020, with election to the Association of American Physicians, which recognizes scientists for the highest caliber of physician-led science accomplishments and scientific leadership.

Theres now a body of research indicating that damaged mitochondria contribute to premature aging, and their implications for human health stretch beyond one illness.

Dysfunctional mitochondria are associated with not only Parkinsons disease, but also other neurodegenerative diseases, cancer, diabetes and heart disease, Guo said. So we asked, Is it possible for us to reverse this damaged mitochondrial signature?

Mitochondria have their own genetic materials distinct from those in the cells nucleus and exploring mitochondrial DNA has become a signature of Guos research. In one of her recent studies, a collaboration with Caltech researchers, Guo and her colleagues discovered how to reverse up to 95% of the damage to mitochondrial DNA in animals.

Among the most recent rewards for her success was an academic career leadership award from the National Institute on Aging that will enable UCLA to establish a new interdisciplinary center, led by Guo, that will focus on aging, mitochondrial health and dementia. The center, which will encompass teaching, research and outreach, will engage faculty members from the Geffen School of Medicine, the UCLA College, the UCLA Samueli School of Engineering, the UCLA Fielding School of Public Health and UCLA-affiliated hospitals.

The new center also will be aligned with theCalifornia NanoSystems Institute at UCLA,of which Guo is a member. The interdisciplinary nature of nanoscience, which concerns phenomena occurring on the scale of billionths of a meter, provides an opportunity to engage physicists, data scientists and engineers who can bring new perspectives to anti-aging research.

CNSI has a strong tradition of innovation and entrepreneurship, which is something I am passionate about, she said.

Indeed, in 2021, Guo was named a UCLA Faculty Innovation Fellow. The fellowship program, a collaboration among Startup UCLA, theUCLA Technology Development Groupand the Office of the Vice Chancellor of Research and Creative Activities, helps UCLA professors develop ideas for companies that are based on their research. Also in 2021, she received a Noble Family Innovation Fund grant from CNSI; the funds support a team of scientists including UCLAs Robert Damoiseaux and Jonathan Wanagat and Caltechs Bruce Hay working on aging research.

One of Guos newest areas of study is exploring PINK1 and PARKIN signaling in the gut. The subject is of interest because digestive issues often precede, by years, the neurological symptoms of Parkinsons. That work, which Guo is conducting with Dr. Elizabeth Videlock, a UCLA assistant clinical professor of digestive diseases, is funded by a 2021 grant from the Chan Zuckerberg Initiative.

Guo said her abilities and insights as a researcher are augmented by her role caring for people with neurodegenerative diseases. She invites some of her patients to speak in her lab, which has dual benefits: Patients see firsthand the scientists who are dedicated to tackling their disorders, and Guos trainees gain a deeper understanding from those who know the diseases inside out.

I love to be connected to patients, she said. They teach me a lot about resilience, about optimism and about life. It gives me an enormous amount of motivation to go back to my lab and identify fundamental causes of these diseases and find cures for these currently incurable diseases and to change the trajectory of aging.

See more here:
To fight diseases of aging, scientist makes aging itself the target - University of California

Introduction

Following a recent update of the definition and classification of inherited metabolic diseases (IMD), more than 1600 IMDs were described (http://www.iembase.org/).1 Although it is frequently presumed that IMDs are uncommon cause of epilepsy or seizures,2,3 timely diagnosis of these diseases is particularly important for several reasons: 1) As many as 600 (37%) IMDs out of 1616 currently described (as of 22.10.2021, accessed through http://www.iembase.org/) may involve epilepsy or seizures as the main or one of many symptoms (Box 1). Only a subset of these IMDs may be diagnosed through conventional metabolic testing, therefore, their true prevalence may have been underestimated in previous metabolic testing-based studies.4,5 Moreover, novel groups of IMDs have recently been defined (eg, congenital disorders of autophagy, disorders of the synaptic vesicle cycle) and many of these novel diseases may present with epilepsy or seizures;6,7 2) Specific etiological treatments are being developed for an increasing number of IMDs and it is imperative to diagnose these diseases and institute treatments in time.8,9 Conventional treatments of epilepsy can be ineffective in some IMDs, while specific etiological treatments (eg, in pyridoxine-dependent epilepsy10 may fundamentally improve patients prognosis and enable fulfilling life for the patient and his/her family. 3) Even in cases where specific treatments are not available, precise diagnosis of IMD may still be highly beneficial to patients and families as it allows halting diagnostic odyssey and avoidance of further, sometimes invasive testing.11 In some cases potentially detrimental treatments may be withheld as in the case of epilepsy due to some mitochondrial diseases where valproates may induce fatal hepatic failure.12 Besides, genetic diagnosis gives prognostic information, enables appropriate targeted long-term follow-up, informed reproductive choices for families, inclusion into clinical trials and engagement into patient organizations.4,13 In cases of refractory epilepsy, identification of germline mutations in specific genes contraindicates surgery while mutations in other genes do not.14 A subset of IMDs is highly amenable to ketogenic dietary treatment.15 Generally, diagnosis of IMD is more likely to change management of a patient compared to other genetic diagnoses: in a recent study of 59 patients with early-onset epilepsy who got the genetic diagnosis through whole exome sequencing (12 of them (20%) were diagnosed with IMD), clinical management following genetic diagnosis was changed in 5 patients with IMD (42% of patients with IMD) and 17 patients without IMD (36% of patients without IMD).16 Therefore, precise diagnosis of IMD is highly important for further multidisciplinary integrated care of patients.

Box 1 Genes Associated with Inherited Metabolic Diseases Involving Epilepsy or Seizures as a Symptom

The vast majority of IMDs that may present with epilepsy or seizures are multisystem, life-long disorders where epilepsy or seizures is just one among many other symptoms. Multidisciplinary care involves all stages of management: diagnostics, acute and chronic treatments, and long-term integrated care for patients with complex needs. Not only medical, but also manifold psychosocial, educational, vocational and other needs of patients and their caregivers must be taken into account.17,18 In this narrative review we investigate various aspects of multidisciplinary care and discuss about some key challenges, opportunities and suggestions for the organization of high-quality care services that meet expectations of patients and families and conform to current patient-centered and value-based care principles. Further research on the overall organization of multidisciplinary, integrated care and various aspects of service provision may enable optimization of complex care and, eventually, better outcomes for IMD patients with epilepsy or seizures and their caregivers.

We performed literature searches using PubMed and Medline electronic databases using the various combinations of the following search terms: epilepsy OR seizures AND inherited metabolic diseases OR inborn errors of metabolism OR multidisciplinary care OR care coordination OR transition of care OR self-management. Further searches were informed by references in the publications and related features in PubMed. Searches were limited to English language and included a period of 2010 to current (October 2021) period.

IMD was defined as any primary genetic condition in which alteration of a biochemical pathway is intrinsic to specific biochemical, clinical and/or pathophysiological features.1

Multidisciplinary care was defined as a care when professionals from a range of disciplines work together to deliver comprehensive care that addresses as many of the patients needs as possible.19

Care coordination involves deliberately organizing patient care activities and sharing information among all of the participants concerned with a patients care to achieve safer and more effective care.20

Care pathways were defined as a complex intervention for the mutual decision-making and organization of care processes for a well-defined group of patients during a well-defined period. Defining characteristics of care pathways include: a) an explicit statement of the goals and key elements of care based on evidence, best practice, and patients expectations and their characteristics; b) the facilitation of the communication among the team members and with patients and families; c) the coordination of the care process by coordinating the roles and sequencing the activities of the multidisciplinary care team, the patients and their relatives; d) the documentation, monitoring, and evaluation of variances and outcomes, and e) the identification of the appropriate resources.21

Patient empowerment was defined as patient engagement through which individuals and communities are able to express their needs, are involved in decision-making, take action to meet those needs.22

Self-management was defined as the interaction of health behaviors and related processes that patients and families engage in to care for a chronic condition.23

Transitional care was defined as the purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented health care systems.24

Palliative care was defined as the active total care of body, mind and spirit, (as well as) giving support to the family. It begins at diagnosis, and continues regardless of whether or not a patient receives treatment directed at the disease.25

Ultra-rare disease was defined as a disease with a prevalence of <1 per 50,000 persons.26

Seizures were defined as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain.27

Epilepsy was defined as a disease of the brain defined by any of the following conditions: (1) At least two unprovoked (or reflex) seizures occurring >24 h apart; (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome.28

Epilepsy syndromes were defined as syndromes that have a typical age of seizure onset, specific seizure types and EEG characteristics and often other features which when taken together allow the specific epilepsy syndrome diagnosis.29

More than 1600 IMDs are currently on the list of IMD classification http://www.icimd.org/; http://www.iembase.org/,1 600 of them (37% of all described IMDs) may present with epilepsy or seizures (Box 1). All these IMDs are rare or ultra-rare diseases, and various stages of their management require highly-specialized services and expert knowledge that goes beyond those available at primary or secondary healthcare level. IMDs presenting with epilepsy or seizures are highly heterogeneous: although involvement of central nervous system (CNS) leads to the most disabling and life-threatening symptoms, any other body system or tissue may also be affected with frequently multisystem presentation.30,31

CNS involvement in these diseases results in a wide spectrum of symptoms including global developmental delay, autism, behavioral problems and intellectual disability,9 other more common neurological presentations include neurodegenerative and movement disorders.32,33 Epilepsy may be a dominating symptom (eg, pyridoxine-dependent epilepsy10 and other developmental and epileptic encephalopathies (DEE) due to IMD),34 or a more variable symptom in a subset of all patients with a given disorder (eg, succinic semialdehyde dehydrogenase deficiency).35 In other cases, symptomatic seizures occur only during acute metabolic decompensation or develop as a consequence of brain damage during metabolic crises (eg, organic acidurias).36 Seizures can be amenable to conventional anti-seizure drugs (ASD), although a substantial number of IMDs are associated with severe and treatment-resistant forms of epilepsy, including DEE34 or status epilepticus.37,38 Presentations of IMDs may be highly diverse, but metabolic etiologies should be considered in unexplained neonatal or infantile seizures, refractory seizures, seizures related to catabolic stress (eg, due to fasting, intercurrent illness or surgeries), multisystem presentation, family history or parental consanguinity.39 The first symptoms of IMDs usually develop in children, however, adolescent or adult-onset presentations are being increasingly identified. Treatments of many IMDs have been optimized leading to an increasing number of patients who survive well into adulthood and, on the other hand, with the improvement of genetic diagnostics IMDs adult persons for whom diagnostics was previously not available, can now be studied.4042 Currently, almost 50% of approximately 33,000 patients in the European Reference Network for IMDs MetabERN are adults.43

Conventional methods for the diagnosis of epilepsy (as seizure semiology, electrophysiological or neuroradiological investigations) may sometimes provide diagnostic clues to IMDs, however, most frequently findings are non-specific.13 Importantly, IMDs may present with any seizure and epilepsy type and any epilepsy syndrome, while some epilepsy-related brain lesions as neuronal migration defects may be due to IMD.44 Precise diagnosis of IMD may be achieved only through metabolic and/or molecular genetic testing that is usually available in specialized laboratories only.4,45

Many IMDs are amenable to specific etiological treatments,9,46 and many new potential personalized therapies are currently at various stages of clinical research and will be presumably translated into clinical practice in coming years.8 Specific treatments include nutritional or vitamin/ cofactor supplementation therapies, relatively inexpensive and frequently highly effective treatment modalities.47 Enzyme replacement and small molecule therapies, stem cell and solid organ transplantations, and cell or gene therapies may also provide opportunities of highly effective specific treatments. It is imperative for clinicians to have a sufficient index of suspicion for these diseases in order to identify and diagnose them in time, as early diagnosis and treatments may prevent major neurological sequelae and enable favorable outcomes.13

Although, to the best of our knowledge, there are no studies that specifically investigate care experiences of patients with IMDs that involve epilepsy or seizures and their families, studies of related patient groups (eg, patients with IMDs, early refractory epilepsy or epilepsy associated with intellectual disability) suggest, that both the overall organization of multidisciplinary, integrated care and various aspects of this care (eg, transition of care or care coordination) are insufficient.18,48,49 Fragmented health and social care systems do not meet expectations and needs of patients and families, there is a lack of support in navigating complex care pathways and insufficient communication among professionals and sectors, especially at transition of care points. Due to the scarcity of knowledge and awareness about these rare diseases, patients and families may be insufficiently provided with the necessary information about the disease, its presumed course, prognosis, possible comorbidities, as well as available services and supports, including psychological support and peer support groups. Patient education, empowerment and inclusion into common decision-making is also lacking.18,50 In some cases developed informational materials do not meet patients and caregivers needs in terms of content and form (eg, preferences of web-based information versus written).51 Importantly, patients and families needs change along the clinical path of the disease, therefore, they have to be assessed repeatedly and addressed accordingly.18 Caregivers of children with IMDs relate that these deficiencies are especially burdensome outside the highly-specialized settings, when encountering professionals unfamiliar with the childs disease.52 A distinctive feature of rare diseases with metabolic and epileptic emergencies is their unpredictability and often associated uncertainty, that evokes even higher anxiety, depression and other psychological and emotional issues of caregivers. These facts associated with difficulties in decision-making demand a close communication with professionals which is sometimes felt by patients as very difficult.17,49,50 Finally, care organization and quality of services is highly unequal across and sometimes within countries.36,53

Due to their multisystem, frequently life-long nature, IMDs that involve epilepsy or seizures usually induce complex long-term needs of patients and their families. The goals of integrated, multidisciplinary care are to place patients and their families at the center of care services planning in order to fully respond to their needs, to address holistically not only health-related but also other (psychological, social, educational, vocational) issues, and to ensure high-quality, accessible and effective services.54 Summarized goals of integrated, multidisciplinary care for patients with IMDs that involve epilepsy or seizures are presented in Box 2.

Box 2 The Goals of Multidisciplinary Care in IMD Patients with Epilepsy or Seizures

Care pathways for these diseases are highly complex and diverse (Figure 1) due to several reasons: 1) Heterogeneity of IMDs that may present with epilepsy or seizures; 2) Diversity in health systems organization and available expertise; 3) Patient and family-related factors (eg, rural vs urban living place or willingness to engage into self-management). Healthcare pathway of any rare disease consists of highly-specialized and less specialized services that may variably involve diagnostics, specific and symptomatic treatments, surveillance, rehabilitation, palliative care, cross-border care, patient empowerment, social and community services. Highly-specialized care services for rare diseases are usually provided in the Centers of Excellence (CoE) with sufficient expertise and infrastructural resources (as equipment and multidisciplinary teams of experts). These services are usually expensive, centralized and provided far away from patients home, therefore, it is highly important to find the right balance between highly-specialized and local services: in all cases where services may be safely provided locally or require continuous provision (eg, psychological and social support), they have to be provided closer to patients home, while ensuring appropriate specialized support when needed, empowerment of local care providers, patients and their families, and effective communication among all care providers.53

Figure 1 Care pathways for IMD patients with epilepsy or seizures.

Comprehensive patient care includes not only healthcare services at different levels of the health system, but also other services to meet the complex needs of patients and their families, including psychological, social, educational and vocational issues, all of which pose significant challenges for care coordination.55 While general practitioners usually lack time, knowledge and resources to ensure multipronged care coordination for patients with rare diseases, (specialist) nurse coordinators or case managers at the CoE and/ or at the primary care level are uniquely positioned to provide appropriate care coordination and management of transitions of care.56 Trusting patient-provider relationship between nurses and patients/ families supports active communication and allows identification of priorities and barriers for integrated care and self-management, enables holistic, proactive management, continuity of care and improved patient outcomes.56,57

Patients with IMDs involving epilepsy or seizures are highly active healthcare users with complex trajectories across care systems and multiple transitions of care across life and disease stages (eg, transition from pediatric to adult services or transition to palliative care). Patients and families face particular challenges at these transition points.43,58 Hence, these transitions have to be anticipated, planned, proactively prepared and discussed with the family and care providers.

IMDs involving epilepsy or seizures frequently present with epilepsy or metabolic decompensation-related emergencies, where timely treatments may determine patients outcomes.36,37 Management of these emergencies evoke particular challenges for families and needs particular consideration from the side of professionals: patients and their families must be able to recognize the first signs of an imminent or occurring emergency, have predefined plans for immediate action (eg, oral emergency regimens for nutritional therapies, emergency seizure protocols) and knowledge on how to monitor the patients condition, when and where to go for emergency care. These plans must also include 24h/7 days contacts for emergency specialist assistance. In some cases, the patient first goes to the nearest hospital; in such cases, it is necessary to ensure proper communication between healthcare providers and transfer of samples or patients to highly-specialized institutions when required.36,50 Widespread availability of evidence-based emergency protocols is highly important; through international collaboration involving MetabERN, generic emergency protocols for patients with fasting intolerance in eight languages and an on-line tool for generating protocols for individual patients were developed (https://www.emergencyprotocol.net/).59

The greatest burden of care for IMDs that involve epilepsy or seizures always falls on the shoulders of patients and/or families, therefore, each care pathway must include empowerment that must be family-centered.60 A lack of consideration of familys needs, including not only direct caregivers but also other family members (eg, siblings) harms their ability to provide effective care and may have detrimental effects on patients outcomes and wellbeing of the whole family.61 Depending on disease, organization of care in a given country and patient/ family-related factors, empowerment includes provision of required information, involvement into common decision-making, patients and familys education, support for self-management, liaison with peer support groups and emotional/ psychological support.18,48,52,62 Self-management is critical for individuals with epilepsy and their caregivers in order to maintain optimal physical, cognitive, and emotional health, especially in cases of refractory epilepsy or handling such challenging treatments as ketogenic diets.63 Although high benefits of these interventions were demonstrated,6466 their implementation is still insufficient and requires considering many factors at the person, program, and systems levels.67

International collaboration is indispensable in addressing various aspects of highly-specialized care for rare diseases, therefore, 24 European Rare Diseases Networks (ERNs) for rare and complex diseases were launched in 2017.68 These ERNs provide virtual and physical cross-border services not available in patients country of origin, moreover, they develop highly required resources for multidisciplinary, integrated care including clinical practice guidelines, educational programmes, recommendations and tools for integrated multidisciplinary care.43,53 Patients with IMDs that involve epilepsy or seizures may require services of several ERNs: MetabERN was developed for patients with IMDs, EpiCARE is for rare epilepsies, ERN-RND is for rare neurological disorders, and TransplantChild may be required in cases where there is a need for liver, stem cell or other transplantations. The accessibility of ERNs must be ensured through the proper organization of care pathways and referral systems towards ERNs.53

Digital technologies have paved the ways for innovative eHealth services, including teleconsultations for patients and professionals, electronic tools for patient monitoring, self-management and education, and more. Although these services are particularly important for patients with rare diseases and can significantly increase the availability of highly-specialized services and expertise, they are often not properly organized, regulated and reimbursed. The pandemic significantly increased the deployment and use of these services across all healthcare areas, including epilepsy care.69 These achievements are expected to be sustained and exploited for the benefit of patients and their families in the post-pandemic period. Besides, recent explosive spread of digital communication technologies enables liaison among rare disease patients and families dispersed across countries and continents and formation of peer support groups that may provide highly required emotional and practical support and advices, empowerment, advocacy and decrease the feelings of abandonment and isolation.60 Therefore, impact of digital technologies on service provision and outcomes should be evaluated and exploitation of these technologies along the entire care pathway where required should be encouraged.

Many IMDs involving epilepsy or seizures are included into neonatal screening programs when they have specific treatments that can improve significantly the prognosis. According to global standards, patients diagnosed through neonatal screening are usually provided with the full range of services that have a big impact on prognosis and quality of life, from screening to diagnosis, institution of treatment, monitoring, and long-term, multidisciplinary management.70 However, some newborns may develop acute symptoms before the results of neonatal screening are obtained, lists of screened IMDs differ among countries, and only a subset of all IMDs presenting with epilepsy or seizures are suitable for neonatal screening.71,72 It is therefore essential for neonatologists to know what diseases are being screened for in their country and where to get the information on IMD screening, diagnostics and expert advice on emergency treatment.

In some infantile-onset epilepsy syndromes, a considerable subset of patients is diagnosed with IMDs: eg, IMDs have been found in 3% to 22% of infants with West syndrome.34 Precise genetic diagnosis in these patients may not only enable specific etiological treatments, but also provide prognostic information and guidance for antiseizure treatment. Impact on psychomotor development and cognitive function may vary between some milder developmental encephalopathies to severe epileptic encephalopathies. Clinicians must tailor care towards individual needs and realistic expectations for each affected person; those with developmental encephalopathies are unlikely to gain from aggressive antiseizure medication whilst those with epileptic encephalopathies will gain.73

Transition to adult care represents a vulnerable time in the life of a patient and his/her family.17,48,49,61 Transition as a purposeful and planned process should address manifold medical, psychosocial, educational, and vocational needs of adolescent and young adult patients as they move from a pediatric to an adult model of care. At the very least, it involves coordination of care between care providers to ensure that the adult providers have sufficient medical and other related information about the patient and his/her family and competence to provide optimal disease management. As much as it is possible, patients should acquire knowledge and skills in the domains of self-care, healthcare decision-making, and self-advocacy in such a way that will prepare them to increase their agency surrounding their healthcare needs.74 In children with IMDs that involve epilepsy or seizures the primary care provider is usually either pediatric neurologist or metabolic pediatrician. While in transition from pediatric to adult neurologist the largest problem may be excessive anxiety of patients and/or families that is completely resolved with the proper organization of transition,75 transition among the specialists of metabolic medicine is frequently complicated due to the lack of specialists for adult IMDs.76 According to the survey of the ERN for IMDs MetabERN, in most European countries transition of pediatric patients and services for adults with IMDs are insufficiently organized.43 Expertise in adult metabolic medicine is lacking worldwide, because education on IMDs in adolescents and adults is inadequate and the specialty is mostly not formally recognized.71 Due to the inherent phenotypic variability of adult IMDs dependent not only from genotype, but also due to the effect of environmental factors, ontogenetic changes and aging and lack of knowledge on many aspects of IMDs associated with prolonged survival and novel treatments (eg, late adverse effects of interventions and definition of new natural histories), the field of adult IMDs is still developing.77,78

An increasing number of females with IMDs that may present with epilepsy or seizures enter reproductive age. Pregnancy and perinatal care-related issues in this group of women are dual and involve: 1) IMD-related issues, eg disease effects on fertility, teratogenic effects of a disease (as phenylketonuria) or medicines, challenges of nutritional treatments and metabolic control, worsening of an underlying maternal IMD due to pregnancy, special recommendations for breastfeeding and IMD effects on labour (as skeletal dysplasia in mucopolysaccharidoses).79 Some IMDs of intermediary metabolism may present for the first time or exacerbate during the perinatal period (eg, urea cycle defects).40 2) epilepsy and ASD treatment-related issues, including teratogenic effects of some ASD, seizure control during the pregnancy and in the perinatal period and other associated issues.80 Therefore, obstetricians gynecologists have to be involved into multidisciplinary teams for the management of females with IMDs.

Patients with life-limiting or life-threatening conditions require timely and family-centered palliative care, especially in a pediatric setting.81 In medical terms, palliative care aims to achieve pain and symptom management, enhanced dignity and quality of life for the patients. Though comfort is often the most common goal identified, symptom identification and treatment remains challenging in nonverbal children with neurological impairments.58 Besides, in IMDs symptom burden is usually high with neurologic, respiratory and gastrointestinal symptoms being the most frequent and most of those being difficult to treat or even intractable.82 Another issue in IMDs, pertinent to any rare disease, is a lack of knowledge and inherent uncertainty about prognosis and medical interventions that may complicate decision-making process.83 Noteworthy, a high number of children with metabolic diseases die in intensive care units. In these cases, an integrated model of care that combines pediatric intensive care and primary pediatric palliative care depending on the disease trajectory might be a fundamental component of the best available standard of care.81

Not only medical, but also ever changing social, psychological, emotional and spiritual needs of the family beyond what the primary care team can provide should be addressed.84,85 Therefore, palliative care should be planned in advance, ideally from the moment of diagnosis, and is best delivered in a team committed to family centered care and open and reflective practice throughout the journey of a childs illness and death, including bereavement period. Quality of relationship and inclusion of a patient and his/her family into a common decision-making are the core elements of palliative care.84,85 Families and professionals should also acknowledge the unique experiences and needs of siblings, include siblings in medical conversations and care plans when appropriate, and connect siblings to resources for informational and emotional support.61

In some cases, diagnosis of an IMD is only achieved post-mortem. Without a clear diagnosis the families find themselves in a very precarious situation, not least regarding end-of-life decisions. For both caregivers and health care professionals, it may be difficult to even consider palliative care because the course of the disease is not predictable Additionally, the lack of a diagnosis raises uncertainty about family planning and the risk of recurrence in future children. In spite of these uncertainties, patients and families have the same rights to receive optimized and symptom-adapted palliative care.83

Due to the complexity and rarity of IMDs, general practitioners (GPs) are usually unable to provide all the necessary information, services, and support, therefore, it is highly important for patients and families to have a named physician supervising them in a highly-specialized setting and a multidisciplinary team that encompass both local/regional and highly-specialized settings (Table 1).45 The specialty of this physician depends on the nature of the disease: where epilepsy or seizures is just the one of many other symptoms or occur only during acute metabolic decompensation, a supervising physician is usually a metabolic pediatrician or a specialist of adult IMDs. In some countries, specialty of metabolic pediatrician is not formalized, while in most countries specialists of adult IMDs are not available or lacking; in these cases functions of supervising highly-specialized physician may be assumed by geneticists or physicians of other specialties.76 When the predominant symptom of IMD is epilepsy, the supervising highly-specialized physician is usually a pediatric or adult neurologist or epileptologist. These specialists - A metabolic pediatrician or other specialist in metabolic diseases, a pediatric or adult neurologist (epileptologist) - usually lead a whole multidisciplinary team that is ideally based in a dedicated CoE. The multidisciplinary team consists of core members providing the main services to patients and families: in the IMD department, these may include laboratory specialists from biochemical genetic and molecular genetics laboratory, geneticists, dietician, specialized nurse or other care coordinator, neonatologist and intensive care specialist, rehabilitation specialists, psychologists, social workers and play specialist/therapist. In the epilepsy department, the multidisciplinary core team usually consists of laboratory specialists, neuroradiologist, neurophysiologist, neurosurgeon. If necessary, the core team is complemented by other extended team specialists, eg obstetrician-gynecologist, physicians of other specialties, pharmacist, etc. The CoE for rare diseases usually carry out not only provision of highly-specialized healthcare services but also education and research and these additional functions also determine the composition of the multidisciplinary team. There is a need for staff to manage rare disease registries and biobanks, to administer research projects, to conduct clinical trials, to provide education and training and to collaborate with various research and educational institutions.

Table 1 Multidisciplinary Teams for Care of IMD Patients with Epilepsy or Seizures

All multidisciplinary team members follow the same clinical practice guidelines (CPGs) or other evidence-based resources, develop and implement individual patient care plans, therefore, it is highly important to ensure proper communication and collaboration among the entire team. In addition, appropriate teams communication with GPs, other care providers across various levels of health and social care systems and appropriate involvement of patients and families are essential, hence, the role of a specialist nurse coordinator or other care coordinator is indispensable.

Multidisciplinary care should also involve primary care and community level: many long-term mental health, physical therapy and rehabilitation, social services for patients and families, services to address educational and vocational issues are inevitably provided at a primary or community level.86

Due to the heterogeneity, multisystem nature and complexity of IMDs, the need for highly-specialized services and expertise, and complex care pathways that cross various health system levels, sectoral and sometimes even national borders, the organization of services for patients with IMDs involving epilepsy or seizures and their families is a challenging task. Although these patients are highly active users of care services and their expectations and needs often remain unmet, very little data for evidence-based governance and principles of care organization are available.53,78 While diagnostic and treatment services are frequently provided simultaneously, precise genetic diagnosis usually establish a crucial landmark for the management of these patients.

Diagnosis of IMDs requires sufficient knowledge and experience and is almost invariably obtained through the highly-specialized laboratory testing. GPs and local healthcare providers typically have neither the expertise nor the resources to diagnose IMD. Unfortunately, the primary healthcare level, which is often the first medical contact point for any patient, often lacks sufficient awareness and index of suspicion for rare diseases and health system literacy on where to refer the patient for specialized services.8789 IMDs are implicated with an additional diagnostic urgency due to the fact that many of them have specific etiological treatments. In order to ensure timely diagnosis and treatment and to reduce diagnostic odyssey, it is necessary to properly organize care pathways and referrals systems towards CoE and ERNs in health systems and to increase IMD awareness and education among care providers.53

Once a precise diagnosis has been established, individual patients care plan must be developed that is not only evidence-based but also meets the individual needs of the patient and his or her family. Unfortunately, CPGs for rare diseases are very scarce,90 while the awareness of and implementation of existing guidelines is clearly deficient and highly unequal across countries.91 Fortunately, ERNs are currently intensively working on the development of novel CPGs for rare diseases and implementation of existing ones.

Depending on the nature of the disease and other factors (such as health system organization, available expertise and resources at primary and local level, patient and family empowerment, etc.), the individual care plans should include initial and follow-up examinations (laboratory and instrumental testing, consultations of specialists), disease monitoring, management of emergencies, family support, genetic counseling and testing, and expected transition points across illness and life stages.

Due to the heterogeneity, multisystem nature and complexity of IMDs, the need for highly-specialized services and expertise, and complex care pathways that cross various health system levels, sectoral and sometimes even national borders, the organization of services for patients with IMDs involving epilepsy or seizures and their families is a challenging task. Multidisciplinary care should place patients and their families at the center of care services planning and to respond to their complex needs, including not only health-related but also other (psychological, social, educational, vocational) issues.

This work was supported (not financially) by the European Reference Networks: European Reference Network on hereditary metabolic disorders (MetabERN). This ERN is co-funded by the European Union within the framework of the Third Health Program ERN-2016Framework Partnership Agreement 20172021.

The authors report no conflicts of interest in this work.

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Patients with inherited metabolic diseases and epilepsy | JMDH - Dove Medical Press

DUBLIN, March 24, 2022 /PRNewswire/ -- The "In situ Hybridization - Global Market Trajectory & Analytics" report has been added to ResearchAndMarkets.com's offering.

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Global In Situ Hybridization (ISH) Market to Reach $1.1 Billion by 2026

Global market for In Situ Hybridization (ISH) estimated at US$846.6 Million in the year 2020, is projected to reach a revised size of US$1.1 Billion by 2026, growing at a CAGR of 5.8% over the analysis period.

The process involved in in situ hybridization is subjecting the cells to some kind of stress to denature the DNA, followed by incubation of the cells containing the denatured DNA in a solution containing labeled probes or sequences whose position on the chromosome is to be determined. In-situ hybridization helps in the precise localization of a specific nucleic acid segment in a histologic specimen.

Fluorescence In Situ Hybridization (FISH), one of the segments analyzed in the report, is projected to grow at a 5.6% CAGR to reach US$885.4 Million by the end of the analysis period. After a thorough analysis of the business implications of the pandemic and its induced economic crisis, growth in the Chromogenic In Situ Hybridization (cish) segment is readjusted to a revised 6.2% CAGR for the next 7-year period. This segment currently accounts for a 28.6% share of the global In Situ Hybridization (ISH) market.

The U.S. Market is Estimated at $361 Million in 2021, While China is Forecast to Reach $79.5 Million by 2026

The In Situ Hybridization (ISH) market in the U.S. is estimated at US$361 Million in the year 2021. The country currently accounts for a 41.52% share in the global market. China, the world second largest economy, is forecast to reach an estimated market size of US$79.5 Million in the year 2026 trailing a CAGR of 7.1% through the analysis period.

Among the other noteworthy geographic markets are Japan and Canada, each forecast to grow at 5% and 5.5% respectively over the analysis period. Within Europe, Germany is forecast to grow at approximately 5.6% CAGR while Rest of European market (as defined in the study) will reach US$85.7 Million by the end of the analysis period.

The market is poised to post healthy growth over the coming years, driven by various favorable factors steering market expansion. Increasing incidence of cancer and genetic abnormalities, need for rapid disease diagnosis through genetic techniques, as well as higher funding (both public and private) leading to introduction of highly advanced cytogenetic techniques and their broadening applications are some of the key factors poised to contribute to future growth.

Story continues

Significant rise in target patient population across the world, and rising preference for CGH in clinical diagnosis, is expected to drive the market further, providing players with lucrative opportunities.

Growing awareness levels of genetic disorders and expanding pool of research laboratories would be beneficial for cytogenetics solutions. Rise in incidence of cancer and the subsequent demand for personalized medicine, is likely to enhance market prospects in a major way.

Key Topics Covered:

I. METHODOLOGY

II. EXECUTIVE SUMMARY

1. MARKET OVERVIEW

Influencer Market Insights

Impact of Covid-19 and a Looming Global Recession

Clinical Diagnostics: Challenges and Opportunities Amid the Pandemic

Research Efforts Underway for Using ISH in COVID-19 Detection

ISH in Molecular Detection of COVID-19 Causing SARS-CoV-2

Immuno RNA Fluorescence ISH for Visualization of COVID-19 Causing SARS-CoV-2

French Research Team Develops CoronaFISH

In Situ Hybridization: A Prelude

Future Prospects Remain Favorable for Insitu Hybridization

Chromogenic ISH: Gaining Over FISH

FISH Technology Continues to Find Favor

How is FISH Better than Conventional Techniques?

Probe Types and Application

Fluorescent In Situ Hybridization Emerges as Cytological Tool of Choice for Plethora of Scientific Applications

Recent Market Activity

World Brands

2. FOCUS ON SELECT PLAYERS (Total 38 Featured)

Abbott Laboratories

Abnova Corporation

Advanced Cell Diagnostics, Inc.

Agilent Technologies Inc

Bio SB

Biocare Medical, LLC

BioGenex Laboratories

Bio-Techne Corporation

Genemed Biotechnologies, Inc.

Leica Biosystems Nussloch GmbH

Thermo Fisher Scientific

Merck KGaA

Oxford Gene Technologies

PerkinElmer Inc.

3. MARKET TRENDS & DRIVERS

Rising Incidence of Cancer Drives the Demand for In-situ Hybridization

Diverse Applications of FISH Technology in Oncology

Growing Demand for Targeted Therapies in Cancer Treatment Presents Lucrative Opportunities

Growing Number of Genetic Disorders and Emphasis on Genetic Testing Bodes Well for the Growth of ISH Market

List of Genetic Disorders by Event, Genetic Manifestation and Prevalence

Top Ten Genetic Diseases Worldwide

Rise in Prenatal Testing Drives Opportunities

FISH in Detection of Prenatal Genetic Abnormalities

In Situ Hybridization Advances Present Perfect Tools to Detect Genetic Anomalies

Uptrend in Companion Diagnostics Market Augurs Well

Companion Diagnostics Lead the Way to Personalized Medicine

State-Sponsored Molecular Research Initiatives Bode Well for Market Growth

Increasing Research on Application of ISH in infectious Disease Diagnostics to Drive Growth

FISH in Detection of Microbiological Pathogens

Growth in In-vitro Diagnostics (IVD) for Diagnosis of Chronic Diseases Promise Opportunities

High Demand for IVD Devices Promises Opportunities for FISH Probes

Rising R&D Investments in the Biotech Sector Drives Gains

Emergence of Automated Diagnostic Kits

Novel Approach of Highly-Multiplexed FISH for In-Situ Genomics

Technology Advancements & Improvements Bolster Growth

Rise in Healthcare Expenditure to Drive Growth

Ageing Demographics to Drive Demand

4. GLOBAL MARKET PERSPECTIVE

III. REGIONAL MARKET ANALYSIS

IV. COMPETITION

For more information about this report visit https://www.researchandmarkets.com/r/1lbes0

Media Contact:

Research and Markets Laura Wood, Senior Manager press@researchandmarkets.com

For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900

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Lesson Overview

Featured Article: In a First, Man Receives a Heart From a Genetically Altered Pig by Roni Caryn Rabin

On Jan. 7, doctors in Maryland successfully transplanted a pigs heart into a human. The breakthrough may lead one day to new supplies of animal organs for transplant into human patients, Roni Caryn Rabin writes.

In this lesson, you will learn about the groundbreaking procedure and consider its place within the greatest medical advancements in history. In Going Further activities, we invite you to research other recent medical breakthroughs and to speculate on how far the field of medicine might extend life.

What, in your opinion, are the greatest medical achievements of all time?

With a partner or small group, brainstorm medical innovations and advances throughout history, such as aspirin, Band-Aids, X-rays, contraceptives and the recent coronavirus vaccine. Which do you think have made the biggest impact, whether by reducing pain, suffering and disease; giving comfort; or extending human life?

Then, choose one advancement from your list and make a one-minute case to the rest of the class for why it could be the single greatest medical achievement of all time.

Read the article, then answer the following questions:

1. Why was an eight-hour surgery in Baltimore on Jan. 7 global news? In your own words, describe what happened and why you believe it is making headlines around the world.

2. Understand the importance of organ replacement by finding some numbers in this article: How many Americans received a transplanted organ last year? How many people received human donor hearts last year? How many people are waiting for kidneys and other organs? And how many people on lists waiting for organs die each day? Taken together, what do these numbers tell you about the need for organ replacements in this country?

3. Who is David Bennett Sr. and why did he decide to gamble on the experimental treatment? Would you ever consider participating in a risky and experimental trial like Mr. Bennett did?

4. The article states that xenotransplantation, the process of grafting or transplanting organs or tissues from animals to humans, has a long history. Which examples from the article did you find most fascinating or significant?

5. Why a pig heart? What advantages do pigs offer over other animals for organ procurements?

6. Dr. David Klassen, the chief medical officer of the United Network for Organ Sharing and a transplant physician, called the news of the successful transplant a watershed event. Do you agree? How significant do you think it is? Return to your list from the warm up. Where would you place this pioneering surgery, or organ transplants more generally, on your list of greatest medical achievements?

7. Do you think that the use of animal organs for human transplants will become commonplace in the next 10 or 20 years? Should they? What ethical questions and concerns, if any, does the article raise for you?

Option 1: Learn more about other medical advances.

A mechanical womb to grow mouse embryos. A drug that brings drastic weight loss to patients with obesity. An unexpected key to understanding hair loss. These are just a few of the recent medical innovations and breakthroughs covered by The Times.

Choose one of the articles below or search for one that grabs your interest on the Timess Health topic page. Then, write or discuss with a partner: What is your reaction to the article? What was the most fascinating, surprising, provocative or memorable thing you learned? What questions do you still have about the scientific breakthrough you read about?

Option 2: Share your thoughts and opinions: How long can medical advancements extend life?

Last century, the average human life expectancy doubled. Medical and social advances such as the development of antibiotics and vaccines reduced childhood deaths, mitigated diseases of old age and vastly prolonged life. In Can We Live to 200?, Nicholas St. Fleur, Chloe Williams and Charlie Wood presented 43 advances that could radically extend life spans over the next 100 years. Look at the interactive timeline, then respond to the following prompts:

Which scientific advancements and breakthroughs in the article do you most look forward to? Which do you think will most likely come to fruition?

By 2100, how long might people be able to live? Do you think humans will reach the ages of 130, 150 or even 200?

Does the possibility of radical life extension intrigue, surprise, excite or even scare you? Would you want to live to 200? How long would you want to live, if you could choose your life span?

If you are interested in joining a conversation with other students, share your thoughts in our related Student Opinion prompt.

Additional Teaching and Learning Opportunities:

Learn more about the science behind the story: Read Heres How Scientists Pulled Off the First Pig-to-Human Heart Transplant from Science.org, which details how the effort involved genetic engineering, an experimental drug and cocaine. How did the article add to or change your understanding of the first successful transplant of a pigs heart into a human? What was most interesting or surprising? What questions do you still have?

Explore bioethical issues further: The Times later reported that Mr. Bennett Sr. had a criminal record stemming from an assault 34 years ago in which he repeatedly stabbed a young man, leaving him paralyzed. The victims brother and people on social media expressed outrage and questioned the choice to select Mr. Bennett as the recipient of the pioneering transplant procedure. However, Karen J. Maschke, a research scholar at the Hastings Center and the editor of the journal Ethics & Human Research, said, Theres a longstanding standard in medical ethics that physicians dont pick and choose who they treat. Read the article and give your reaction: How should we decide who receives a lifesaving treatment? Should a patients history affect the decision? Why or why not?

Want more Lessons of the Day? You can find them all here.

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Lesson of the Day:In a First, Man Receives a Heart From a Genetically Altered Pig - The New York Times

A team led by collaborating researchers from Weill Cornell Medicine, Weill Cornell MedicineQatar and Qatar Foundation have assembled a large genomic database on the Qatari people, and have used it to develop an advanced but low-cost screening tool for genetic diseases in this highly distinct Middle Eastern population.

The tool, QChip1, is a microarray capable of detecting, from a blood sample, more than 80,000 different DNA variations in genes linked to hereditary disorders. Costing less than $100 each, QChip1 microarrays will be used to evaluate the risks of such disorders among newborns, couples planning a family and hospital patientsthus advancing personalized medicine in Qatar.

As the researchers demonstrated in their study, published Jan. 19 in npj Genomic Medicine, a population-specific screening tool is necessary in Qatar because the Qatari population has a largely distinct set of genetic disorder risk variants, 85 percent of which are not seen in Western populations.

The important message here is that advancing precision medicine with genetic screening tools for a given population requires an understanding of the specific set of risk variants found in that population, said study co-senior author Dr. Ronald Crystal, chairman of the Department of Genetic Medicine and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine in New York, and attending physician at NewYork-Presbyterian/Weill Cornell Medical Center.

The genomic database of the Qatari population and the QChip technology provide an extremely accessible, low-cost and powerful resource for reducing the incidence of a wide variety of inherited diseases, said co-first author Dr. Amal Robay, an assistant professor of research in genetic medicine at Weill Cornell Medicine-Qatar. We are so pleased to have been able to work on this project with our gifted colleagues at Weill Cornell Medicine in New York and closer to home at Qatar Foundation to help deliver this important precision screening tool for the Qatari population.

The QChip1 screening array marks several key milestones for Qatar, said study co-author Dr. Khalid Fakhro, chief of research at Sidra Medicine. First, it represents a significant outcome of Qatars early investment in generating genomic knowledge on our population. Second, this array is a first for the region, and can be adopted by neighboring countries whose populations share ancestry (and disease mutations) with ours. And finally, it demonstrates the strength of collaboration across the biomedical research community in Qatar, as this truly took a multi-stakeholder effort over several years to achieve a viable product, which will completely transform disease screening for future generations.

Other institutions in the collaboration included Weill Cornell MedicineQatar, Qatar Foundation, Sidra Medicine and Hamad Medical Corporation.

The cooperation between multiple institutions is helping produce powerful screening tools, and the impact is not only reflected in the power of numbers, but also in the power of science, said co-first author Dr. Radja Messai-Badji, genomics operations manager at Qatar Foundations Qatar Genome Program. When each entity serves its role within its niche specialty, it leads to well-designed and constantly evolving products for the area of precision medicine.

Thousands of hereditary human disorders, affecting in total about one percent of the human population, arise from pathogenic DNA variations within single genes. These single-gene disorders (SGD) can either be dominant or recessive. For dominant SGDs, the patient can inherit the copy of the gene containing a pathogenic variant from either parent, while for recessive SGDs, the patient needs to inherit the pathogenic variant from both parents in order to manifest symptoms of the disease. Thus, two unaffected parents can be carriers of the pathogenic variant and give birth to an affected child with a 25 percent possibility.

In order to avoid this unexpected scenario, SGD risk variant screening of newborns, and couples who are planning a family, has long been routine in many countries, at least for more serious SGDs such as sickle-cell anemia. Most databases of SGD risk variants and related screening tools were developed for Western populations, though. SGDs are generally the same across human populations, but the precise DNA changes that give rise to those SGDs are often different from one population to another. Researchers also recognize now that in general, more comprehensive screening could enable more personalized and effective medicine.

Qatar is a good candidate for comprehensive and population-specific screening. It is a small country on the Persian Gulf where, in the native population, intra-clan marriage is the norm and about a third of marriages are between first cousinswhich means that marriages often bring together two people who carry the same SGD risk variant inherited from a shared ancestor.

SGD risk screening has a lot of potential, not only clinically for personalized medicine and family planning, but also scientifically for understanding rare genetic diseases, said co-first author Dr. Juan Rodriguez-Flores, an assistant professor of research in genetic medicine at Weill Cornell Medicine in New York. But as this study shows, the development of such tools going forward is going to require genomic databases and screening technologies that are tailored for distinct ancestry groupsand for most groups those tools dont yet exist.

In the study, the researchers assembled a large dataset, from their own and others sequencing of DNA from more than 8,000 Qataris, to construct the Qatari Genome Knowledgebase of known risk variants.

Out of the millions of recorded variants in the Knowledgebase, they selected 83,542 known or likely disease-causing variants, in a total of 3,438 genes, to generate the probes for QChip1. Chips such as these are called genotyping microarrays, and contain arrays of short DNA strands each of which will bind to and register the presence of a DNA sequence of interest.

The researchers demonstrated QChip1 screening by using the chip to analyze DNA from 2,707 Qataris. In this large sample of individuals, they identified a total of 32,674 distinct risk variants, with an average of 134 risk variants per individual. They also found that these variants were relatively Qatari-specific, only about 15 percent of the variants being present in comparative DNA samples from European Americans, South Asian Americans, African Americans and Puerto Ricans. Even in samples from nearby Kuwait, Iran, and the United Arab Emirates, only about half of the detected Qatari variants were evident.

Every day we discover more pathogenic variants, which are observed in some countries to be different from the variant observed in other countries, said co-senior author Dr. Asmaa AlThani, chair of Qatar Genome Program at Qatar Foundation and vice chair of Qatar Biobank Board. Differences between pathogenic variants in different countries are reported on a daily basis, which keeps driving us to pursue our work in genomics, and focusing on pathogenic evolution and potentially pathogenic variants. With every new variant we observe as unique to Qatar, we take on step forward towards better health care, not only for Qatar, but also for other Middle Eastern populations. In order to provide researchers and clinicians access to data for research, the QChip Knowledgebase and the Qatar Genome Browser were constructed, and will keep expanding as more public data and literature from Qatar becomes available.

This groundbreaking effort led by Weill Cornell Medicine highlights the effectiveness and translatability of omics and, in particular, genomic projects such as the QChip to implement precision medicine solutions that are likely to improve health care for the populations of Qatar and the wider region, said study co-author Dr. Khaled Machaca, senior associate dean for research, innovations and commercialization and a professor of physiology and biophysics at Weill Cornell Medicine-Qatar.

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Qatar Project Highlights the Importance of Population-Specific Genetic Screening Tools for Personalized Medicine - Weill Cornell Medicine Newsroom

Messenger RNA (mRNA) technology became a household name so quickly thanks to the COVID-19 vaccines by Pfizer-BioNTech and Moderna, and, now, biotech leaders are taking a moment to reflect on where the field goes from here.

When so much progress has been made, as the past two years, which is objectively astonishing, it can be hard to realize that it's also the beginning, said Geoffrey von Maltzahn, Ph.D., co-founder, and CEO of Tessera Therapeutics, during a Fierce JPM Week panel on "The Next mRNA Wave."

Now, companies that were involved in mRNA before the pandemic have a validated platform on their hands to develop new therapeutics and vaccines, which leads to the inevitable question: What comes next?

mRNA is not new, but it's still in infancy, said Jean-Francois Toussaint, Ph.D., head of research and development for Sanofi Pasteur. There is room to improve it much further down the road, and that's what we are doing.

mRNAs are essentially copies of genetic instructions that can direct your body to make proteins that can then be used to fight or prevent disease. This technology can be harnessed in multiple ways to create different types of medicines. Tessera, for instance, is combining the idea with genetic medicine to allow modifications to the genome that were previously thought to be difficult or impossible.

RELATED: With $3.2B, Sanofi takes in mRNA partner Translate Bio in buyout

Ultragenyx, meanwhile, is focusing on protein replacement using mRNA as a delivery mechanism, according to Chief Medical Officer Camille Bedrosian, M.D.

Sanofi is focusing its research on vaccines that can be implemented into regular inoculation schedulesthink RSV, acne vaccines or potentially chlamydia, according to Toussaint. But where Sanofi really wants to make an impact is on improving the known challenges of mRNA: storage and tolerability.

A known issue with the COVID-19 vaccines has been the side effects a day or so after, when many patients report headaches, chills or even fever. This is absolutely an acceptable outcome in a global pandemic where the need to protect against a deadly disease is so great, but Toussaint said these kinks have to be worked out for the next generation of therapies and vaccines.

Vaccines are given to people that are healthy people that go to work every day, and of course, you don't want them to miss work; you don't want them to stay in bed for one day because they received a vaccine, Toussaint said.

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Von Maltzahn remembers just five years ago more than a few whispers that this would never work. Just before the pandemic, there were more than a dozen clinical trials underway with mRNA involved in some way, and the modality seemed to have landed on a trajectory toward becoming a major part of drug development someday.

It's kind of hard to go pre-moon landing and remember all of the challenges that it took to get onto the moon, von Maltzahn said. But those challenges were plentiful: manufacturing and delivery chief among them.

Now, in the third year of the pandemic, the modality has been accelerated by at least five years to a decade, according to von Maltzahn.

Lipid nanoparticle compositions have now been administered to probably more people than all biologicals, he said, referring to the delivery system that underpins the mRNA-based COVID-19 vaccines.

RELATED: The mRNA era has arrived thanks to COVID-19. What's next in the pipeline?

As Sanofi tinkers with improving the mRNA model, Toussaint said one key part of the delivery equation could be solving the cold storage requirements that initially limited the launch of vaccines from Pfizer-BioNTech and Moderna to major centers that had the proper equipment.

The COVID-19 vaccines certainly accelerated the field, but, because they were approved via emergency use authorizations that are slowly turning into full approvals, their path to market may not be a great comparison for therapies to come. But theres one very important way the shots have helped: awareness.

Ultragenyx recently advanced an mRNA therapeutic for glycogen storage disease type III into the clinic, according to Bedrosian. She shared the story of a patient who asked, When can I get my GST 3 vaccine?

mRNA was a foreign concept. It rolls off the tongue of everybody in the country and in the world now, she said.

Toussaint also suspects regulators will be more comfortable with mRNA therapies and vaccines to come.

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Now that the delivery challenges have been for the most part resolvedwith, of course, room to improve and build on the current methodvon Maltzahn thinks mRNA is poised to have applications across medicine.

It's fairly easy to speculate that we're going to open up multiple categories of new medicines as the field advances, he said.

And on delivery mechanisms, he added, that's probably an unheralded success in what we've called mRNA vaccines. We might have called them lipid nanoparticle vaccines.

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Fierce JPM Week: After 'objectively astonishing' progress on mRNA, biotech looks to tinker with winning formula - FierceBiotech

A study conducted by the Department of Twin Research and Genetic Epidemiology at Kings College London and the National Institute for Health Research (NIHR) BioResource has uncovered new insights on the genetic mechanisms controlling human metabolism. The study analysed the plasma levels of 722 metabolites from blood samples provided by 8,809 European subjects, making it the largest genome-wide association study of metabolite levels to date. Due to the scale of the analyses, the study identified 74 novel genomic regions, influencing human metabolism, that had not been recognised in any previous literature. The findings, which have been published in the journal Metabolites, could aid in the development of precision medicines for conditions such as obesity.

While precision medicines that are tailored to patients genetic profiles have revolutionised the treatment of many cancers, this approach has yet to be applied in clinical practice to conditions like obesity. At present, the dominant therapeutic strategy in obesity pharmacological management involves targeting the glucagon-like peptide 1 receptor (GLP1R), which has the effect of regulating appetite. This mechanism is employed by Novo Nordisks Saxenda (liraglutide), which has remained a leading global therapy in obesity since 2014, as well as Saxendas successor Wegovy (semaglutide), which was launched in the US in June last year.

Wegovy subsequently received approval in the UK and Canada and has been recommended for marketing authorisation by the European Medicines Agencys Committee for Medicinal Products for Human Use (CHMP). The drug, which demonstrated unprecedented efficacy results in Phase III trials and boasts a convenient once-weekly dosing regimen, has generated a great deal of interest within the obesity field. Despite some initial manufacturing issues that will lead to a short supply of the drug in the US in the first half of this year, Wegovy is expected to attain blockbuster status in the near future.

Although Novo Nordisk is currently dominating the obesity market, a wide range of other companies are attempting to enter this space. According to GlobalDatas pipeline products database, there are 233 companies active within the research and development (R&D) landscape that are collectively developing 363 investigational candidates. In addition to its substantial size, the obesity pipeline is also diverse, with 150 distinct molecular targets identified.

While the size and diversity of the pipeline are encouraging, new companies entering the R&D landscape may face an intense level of competition. Obesity is a condition associated with significant heterogeneity, however. Investing in therapies capable of demonstrating strong efficacy or reduced side effects in specific patient subsets could set new players apart from the competition, potentially enabling them to monopolise certain subsections of the market.

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Is precision medicine the future of obesity treatment? - Clinical Trials Arena

NEW YORK A team from Japan has detected loss-of-function mutations in a gene involved in protein homeostasis that appear to contribute to juvenile-onset forms of dilated cardiomyopathy, a heart condition affecting ventricular dilation and systolic dysfunction that can lead to heart failure and the need for a heart transplant.

"Familial DCM is reportedly caused by mutations in more than 50 genes, requiring a precise disease stratification based on genetic information," senior and corresponding author Yoshihiro Asano, a cardiovascular medicine researcher at the Osaka University, and his co-authors explained in Science Translational Medicine on Wednesday, reasoning that "[i]dentifying the further genetic causes of DCM could improve the utility of genetic testing and might lead to new insights into the pathogenesis of heart failure."

As part of the "Genome registry and stratification of cardiovascular disease" (GRAND-STAR) study, the researchers searched for new contributors to inherited DCM, including mutations in genes associated with heart sarcomeres, cytoskeleton, and other structures.

Along with genetic clues found in exome sequence data for more than 1,800 individuals represented in the GRAND-STAR database, they used RNA sequencing to profile transcriptional features in heart tissue samples from three inherited DCM patients and as many unaffected controls.

By focusing on genes containing rare variants that were upregulated in DCM cases with heart failure, the team identified five individuals with severe DCM from four families who carried truncating, loss-of-function mutations affecting both copies of the BAG5 gene, which codes for a heat shock cognate (HSC70) protein nucleotide exchange factor from the Bd-2-associated athanogene, or BAG,protein family.

In mouse model experiments, the group saw signs that the introduction of BAG5 alterations stymied HSC70 activation a process previously linked to protein homeostasis, or proteostasis and led to DCM-like symptoms in the mice.

The researchers were able to reverse such features by treating the mutant mice with adeno-associated virus serotype 9, or AAV9,viral vectors containing a wild-type version of BAG5 and a cardiac troponin T promoter. Based on such findings, they suggested that gene therapy strategies may eventually preclude the need for heart transplantation in a subset of inherited DCM patients with mutations that lop out BAG5.

"[W]e demonstrated that BAG5 mutations led to loss of functional BAG5 protein, which could be restored through administration of an AAV9-BAG5 vector in a murine model," the authors reported. "This finding suggests that AAV gene therapy should be further investigated as a possible treatment alternative to heart transplantation for patients who are BAG5 deficient."

The researchers noted that hereditary DCM stems from autosomal recessive inheritance of the BAG5 mutations. Even so, they tracked down truncating mutations affecting one copy of the BAG5 gene in three individuals with a reversible DCM subtype called tachycardia-induced cardiomyopathy. The results hinted that heterozygous BAG5 alterations may contribute to TIC, though they cautioned that "the effect of BAG5 mutations on TIC needs to be analyzed in larger groups of patients."

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Dilated Cardiomyopathy Gene Mutations Point to Possible Therapeutic Strategy - GenomeWeb

Dive Brief:

As 2021 began, Huntington's drug research appeared to be on the verge of turning a corner.

Both Roche and Wave Life Sciences were advancing drugs that were similarly designed to block production of a protein implicated in disease progression. For Roche, the stakes were particularly high: A successful result could've led to an approval application for the first drug that might slow the march of the deadly, inherited disease.

By the end of the first quarter, however, both companies reported negative data, raising questions about their drugs as well as researchers' understanding of Huntington's. It also dialed up pressure on companies with earlier stage projects, such as UniQure and Passage Bio.

But it turns out Roche isn't done with tominersen after all, a decision that could have implications for others. While the new clinical trial will be a small, Phase 2 test that will require follow-up studies, tominersen remains one of the most advanced disease-modifying drug in clinical development for Huntington's.

The Swiss drugmaker is in "the early stages" of designing the new trial, Ionis said, which will evaluate different doses of tominersen in younger patients with less severe disease. Roche will share the design of the trial with Huntington's disease specialists in medical meetings later this year, according to Ionis.

Ahead of the trial design presentations, Roche later this week will begin a series of webinars to discuss with Huntington's specialists the after-the-fact analysis of GENERATION-HD1 that hinted at a benefit for the younger, less severe patients.

Roche's Huntington's collaboration with Ionis dates back to 2013, when the big drugmaker acquired initial licensing rights for $30 million and promised up to $362 million in future payouts. Following positive signs in early testing, Roche paid $45 million to license tominersen and cover clinical development as well as commercial costs.

As a disease caused by an identifiable genetic defect, Huntington's seems to be a good target for a medicine that can block the mutation, which results in a flawed version of a protein called huntingtin. Tominersen is a type of medicine known as antisense oligonucleotide and works by going after the RNA that encodes for the protein.

Gene therapies are also aimed at the disease's genetic cause, but work by replacing the defective gene with what could in theory be a one-time treatment. Tominersen, by comparison, was given to patients once every eight or 16 weeks in GENERATION-HD1.

An estimated 41,000 people in the U.S. have Huntington's disease, although many are undiagnosed.

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Roche revives a closely watched Huntington's disease drug - BioPharma Dive

Enveda CEOViswa Colluru, Ph.D./Courtesy Enveda Biosciences

Two-year-old biotech company Enveda Biosciences believes the answers to humanitys most challenging diseases can be found by harnessing the complexity of the natural world. Envedas home base in Boulder, Colorado where many ponder the wonders of the Rocky Mountains every day could not be more fitting.

For centuries, human societies have been using plant-based and other natural products to treat illness, but as Enveda Founder and CEO Viswa Colluru, Ph.D. told BioSpace, we are in a different place today than we were in the late 1990s when interest in biochemistry and natural products first peaked. Indeed, in 2019, when Colluru founded Enveda, machine learning and computational metabolomics had finally arrived, and he wanted to leverage both to their full potential to uncover the fundamental biology of disease and speed up the drug discovery process.

We started Enveda with the vision to build the first high-resolution chemical map of planet Earth and change where we look for new medicines, Colluru said. Because if you ask me, the most powerful library on Earth is one that has spent about 4 billion years in evolution.

Enveda plans to maximize this library by specifically modulating previously inaccessiblebiology, such as undruggable proteins, RNA, or even microbes for therapeutic use. The companys platform is made up of two parts; the first, a Google-like chemical search engine with an algorithm that can directly predict structure from mass spectrometry. This search engine takes the chemistry in the world of which 95% remains unknown and allows Enveda to draw insights from those compounds at scale without needing to isolate each one. It can then determine the specific activity and therapeutic potential of each compound drawing on high-throughput biological experiments conducted in Envedas labs.

The second piece is the knowledge graph, which Colluru called the largest digitized knowledge base of humanity's use of plants as medicine integrated into all of modern biochemistry. Through this technology, Enveda is identifying how new regions of chemical space could drive drug discovery for specific diseases. It takes about 16 million relationships of all known proteins, cellular processes and disease symptoms, and maps it to our data, he explained. One compound, for example, might have an anti-inflammatory effect in the brain and could be useful for treating Parkinsons disease.

During just Envedas first screening campaign for the target, the team uncovered a potential source of a small molecule to modulate Proprotein convertase subtilisin/kexin type 9 (PCSK9), which Colluru described as a holy grail cardiometabolic target. Inflammasome pathway modulators were another big discovery. By studying the protein targets they bind, weve rediscovered known but undrugged inflammasome pathway targets and many potential new ones, he shared.

So, why this specific approach to drug discovery? The answer, Colluru said, is found in historical success rates. Natural products or their derivatives account for one-third of all approved small molecule medicines. This, despite science having only discovered about 150,000 natural products to date. Colluru contrasted that with synthetic libraries, through which large pharmaceutical companies screen roughly 5 to 8 million compounds, accounting for the other two-thirds. If you do the math, historically, natural products have been 10 times more successful at yielding an approved medicine.

Colluru gave his theory as to why this is.

Many of the sources of natural compounds, plants, for example, have co-evolved withcomplex life. Plants can't stand up and walk away from an environment they don't like, so instead, they produce a lot of compounds that allow them to modulate their environment. This environment consisted of microbes, insects, and even mammals. Today, we know that we have as much if not more microbial DNA in our own body and our proteins share homology with those of other mammals. This makes nature a much more relevant chemical dataset, he said, emphasizing that only about 5% of the chemistry on Earth is known. So, imagine what the other 95% would do for drug discovery and beyond.

To accomplish this ambitious mission, Colluru has brought on an executive team with serious gravitas. Theres Sotirios Karathanasis, Ph.D., chief science officer, who comes to Enveda following stints as CSO at Eli Lilly and vice president and head of biosciences at AstraZeneca, and Bryan Norman, Ph.D., VP of drug discovery, who spent 25 years leading drug discovery efforts at Lilly and Searle.

For Karathanasis, the time to maximize natural products in therapeutics is here.

"While it is common knowledge that natural products have historically been a productive source of new drugs, the consistency of active compound discovery from natural products has been challenging. Advanced technologies, including large-scale untargeted metabolomics and modern machine learning algorithms, are overcoming this challenge to provide novel, evolution-optimized pharmacophores for the treatment of multiple diseases, he said. Characterization of these compounds also provides unique opportunities for discovery of fundamental biology analogous to the discovery of the mTOR pathway using Rapamycin and last years Nobel-winning discovery of pain mechanisms using Capsaicin. If Enveda's platform had existed when I was leading large teams in big pharma, we may never have moved away from natural products."

Then, there is Colluru himself who brings his formative experience from Recursion Pharmaceuticals, a unicorn known for integrating technological innovations across biology, chemistry, automation, data science and engineering. Recently, Enveda tapped August Allen, whom Colluru knew from his Recursion days, as chief platform officer. This is a relatively new role in biotech, but one Colluru said is the right fit for Enveda.

Our fundamental strength as a company is our differentiated technology platform, he said. The goal of the chief platform officer is to operationalize and scale the execution of our platform and generate data which in turn feeds its evolution. August joins us after several very impactful years at Recursion, scaling their platform from its very earliest stages.

The foundation for much of Envedas science is based upon the work of Pieter Dorrestein, Ph.D., a leading computational metabolomics researcher and Envedas scientific co-founder. Dorrestein, a professor at the University of California San Diego (UCSD), built the first cloud-scale repositories for mass spec data, along with an algorithm that was able to analyze the entire repository, regardless of whether the identity of the chemical was known.

Envedas therapeutic scope is driven by the lack of success in complex diseases from traditional ways of thinking about single targets or modalities, Colluru said. The company is prioritizing therapeutic targets in the cardiovascular, metabolic and neurological spaces where Enveda has an entry point to a rare disease or those that have shared mechanisms with a rare indication. Two examples of this are Parkinsons and Amyotrophic Lateral Sclerosis (ALS), both of which Enveda is in the early stages of exploring.

In order to offer the maximum benefit for patients, Enveda is exploring partnerships with companies that bring complementary expertise in disease areas outside of its immediate scope. This could include indications such as respiratory disease or large diseases in the cardiometabolic space, Colluru said.

We recognize that the biggest outcome for patients is likely from being able to use all of the excess productivity of our platform, Colluru said. Right now, it is producing more chemical substrate and exciting early data than we know what to do with.

While Envedas short-term objective is to discover new natural small molecule therapeutics, Colluru sees broader long-term potential for the platform.

One application could be using the algorithm to predict unknown metabolites in blood. That will herald a new era of precision medicine, based not on genomics, but on metabolomics, he said. Another potential use is in agriculture, as natures metabolites could inform the functions of nature, enabling an understanding of the basis of food, nutrition, taste and pest resistance. This could become particularly relevant as climate change continues to impact the world.

Another potential breakthrough is the identification of chemical fingerprints, which could have applications in forensics. Just like we all have our DNA fingerprints, we all have our chemical fingerprints, and this is very different from our physical fingerprint or genetic fingerprint. Dorrestein published a paper showing that it was possible to track the cosmetics used on the human body for several days.

Since founding Enveda with $70 thousand of his own savings, Colluru and his team have been on what many would call a remarkable pace. In June 2021, the company raised $51M in a Series A funding round led by Lux Capital. Enveda also found its way into BioSpaces NextGen Bio Class of 2022, a list of the most promising recently-launched life sciences companies in North America.

Colluru credits this rapid progress to two factors: one, hiring amazing people, and then, creating the culture and the habit of getting out of their way, and two; learning to get comfortable with uncertainty. I think it is very, very unlikely that you'll ever be able to see the full staircase, but that should never stop you from taking the first two steps. At Enveda, we have the attitude and culture that we're okay venturing into the unknown, and as a result, it's driven a lot of our discoveries and success.

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Searching for Medicine's Answers in the Most Powerful Library on Earth - BioSpace