HOUSTON A multicenter research team co-led by The University of Texas MD Anderson Cancer Center developed the first drug to treat the uncontrolled secretion of mucins in the airways, which causes potentially life-threatening symptoms in millions of Americans with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), as well as lung disease resulting from cancer and cancer treatment. The study was published today in Nature.

Mucus is a significant problem in pulmonary medicine, because in people with these common lung diseases, thick mucus can block the airways and cause symptoms ranging from a mild cough to very serious decreases in lung function, said Burton Dickey, M.D., professor of Pulmonary Medicine and co-corresponding author of the study. Most drugs for these conditions work to reduce inflammation or expand the airways to help people breathe better, but mucus is the most serious issue. Our research has created the first drug that would stop the secretion of mucins in its tracks.

Muco-obstructive lung diseases affect hundreds of millions of people worldwide. In the U.S., about 25 million people have asthma, 16 million adults have been diagnosed with COPD and CF is the most common life-threatening, genetic disease. Many cancer patients end up with lung disease because their cancer treatments or the cancer itself leaves them immunocompromised.

Normally, mucins are gradually released into the airways, where they absorb water and form a thin layer of protective mucus that traps pathogens and is easily cleared by cilia. In muco-obstructive lung diseases, high volumes of mucins are suddenly released and, unable to absorb enough water, result in a thick mucus that can plug airways and impair lung function.

Dickeys lab began studying mucin secretion two decades ago and previously identified the key genes and proteins involved, showing how synaptotagmin and a SNARE complex, similar to that found in neurons, contribute to the key process of Ca2+-triggered membrane fusion.

We built up a picture of what the secretory machinery looked like and we knew all of the major players, Dickey said. Once we had an idea of how all the pieces worked together, we determined synaptotagmin-2 (Syt2) was the best protein to target to block mucin secretion because it only becomes activated with a high level of stimulation. Therefore, blocking the activity of Syt2 should prevent sudden massive mucin release without impairing slow, steady baseline mucin secretion that is required for airway health.

In this study, a collaborative effort between MD Anderson, Stanford Medicine and Ulm University, the researchers verified Syt2 as a viable therapeutic target protein in several types of preclinical models. Philip Jones, Ph.D., vice president of Therapeutics Discovery and head of the Institute for Applied Cancer Science, designed a hydrocarbon-stapled peptide, SP9, to block Syt2, based on structures developed by the Stanford collaborators, including senior co-corresponding author Axel Brunger, Ph.D., professor of Molecular and Cellular Physiology.

Stapled peptides are a recent therapeutic development involving modified amino acids that form hydrocarbon crossbridges to hold their structure rigid so they can bind to a protein target and show enhanced stability. Stapled peptides have been used to treat other diseases, including cancer, but SP9 would represent the first stapled peptide to be used as an inhaled therapeutic.

In a reconstituted system model in Brungers Stanford laboratory, Ying Lai, Ph.D., used SP9 to successfully disrupt Ca2+-triggered membrane fusion. The Ulm laboratory of Manfred Frick, Ph.D., used SP9 conjugated to a cell penetrating peptide in cultured epithelial cells to inhibit rapid mucin secretion. The Dickey laboratory then used an aerosolized version in a mouse model to confirm the drug reduced mucin secretion and airway blockage by mucus. Importantly, SP9 did not affect the slow-release pathway for normal mucin secretion.

An inhaled drug like this could help someone during an acute attack of airway disease by stopping the rapid secretion of mucin and, by extension, avoiding production of thick mucus. You cant move air through an airway thats plugged, Dickey said. In asthma, COPD and CF, its been shown that persistent plugs drive the most serious disease. Now we have a drug that could be very important if its shown to work in clinical trials.

The stapled peptide SP9 will be further refined before moving to human studies, as is typical for therapeutics at this stage of development, and may enter clinical trials in a couple of years.

Dickey and co-authors are inventors on a patent application related to SP9. The study was supported by the National Institutes of Health (R01 HL129795, R21 AI137319) and the Cystic Fibrosis Foundation. A full list of co-authors and their disclosures is available in the paper.

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Inhibition of calcium-triggered secretion by hydrocarbon-stapled peptides

23-Mar-2022

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Novel therapy could help people with asthma, COPD, cystic fibrosis and cancer-related lung disease - EurekAlert

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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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

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