Company signs option agreement with The Rockefeller University to access intellectual property covering compounds targeting key regeneration pathway

Decibel Therapeutics, a development-stage biotechnology company developing novel therapeutics for hearing loss and balance disorders, today announced a new strategic research focus on regenerative medicine approaches for the inner ear. The company is also announcing a collaboration and option agreement that gives Decibel exclusive access to novel compounds targeting proteins in a critical regenerative pathway.

Decibels research focus on regeneration will be powered by the companys research and translation platform. The company has built one of the most sophisticated single cell genomics and bioinformatics platforms in the industry to identify and validate targets. Decibel has also developed unique insights into regulatory pathways and inner ear delivery mechanisms that together enable precise control over gene expression in the inner ear and differentiate its AAV-based gene therapy programs.

"Our deep understanding of the biology of the inner ear and our advanced technological capabilities come together to create a powerful platform for regenerative medicine therapies for hearing and balance disorders," said Laurence Reid, Ph.D., acting CEO of Decibel. "We see an exciting opportunity to leverage this platform to address a broad range of hearing and balance disorders that severely compromise quality of life for hundreds of millions of people around the world."

The first program in Decibels regeneration portfolio aims to restore balance function using an AAV-based gene therapy (DB-201), which utilizes a cell-specific promoter to selectively deliver a regeneration-promoting gene to target cells. In collaboration with Regeneron Pharmaceuticals, Decibel will initially evaluate DB-201 as a treatment for bilateral vestibulopathy, a debilitating condition that significantly impairs balance, mobility, and stability of vision. Ultimately, this program may have applicability in a broad range of age-related balance disorders. There are currently no approved medicines to restore balance. Decibel expects to initiate IND-enabling experiments for this program in the first half of 2020.

Decibel is also pursuing novel targets for the regeneration of critical cells in both the vestibule and cochlea of the inner ear; these targets may be addressable by gene therapy or other therapeutic modalities. As a key component of that program, Decibel today announced an exclusive worldwide option agreement with The Rockefeller University, which has discovered a novel series of small-molecule LATS inhibitors. LATS kinases are a core component of the Hippo signaling pathway, which plays a key role in regulating both tissue regeneration and the proliferation of cells in the inner ear that are crucial to hearing and balance. The agreement gives Decibel an exclusive option to license this series of compounds across all therapeutic areas.

The agreement also establishes a research collaboration between Decibel and A. James Hudspeth, M.D., Ph.D., the F.M. Kirby Professor at The Rockefeller University and the director of the F.M. Kirby Center for Sensory Neuroscience. Dr. Hudspeth is a world-renowned neuroscientist, a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and a Howard Hughes Medical Institute investigator. Dr. Hudspeth has been the recipient of numerous prestigious awards, including the 2018 Kavli Prize in Neuroscience.

"Rockefeller scientists are at the leading edge of discovery, and we are excited to see the work of Dr. Hudspeth move forward in partnership with Decibel," said Jeanne Farrell, Ph.D., associate vice president for technology advancement at The Rockefeller University. "The ambitious pursuit of harnessing the power of regenerative medicine to create a new option for patients with hearing loss could transform how we address this unmet medical need in the future."

In parallel with its new research focus on regenerative strategies, Decibel will continue to advance key priority preclinical and clinical programs. DB-020, the companys clinical-stage candidate designed to prevent hearing damage in people receiving cisplatin chemotherapy, is in an ongoing Phase 1b trial. Decibel will also continue to progress DB-OTO, a gene therapy for the treatment of genetic congenital deafness, which is being developed in partnership with Regeneron Pharmaceuticals. The DB-OTO program aims to restore hearing to people born with profound hearing loss due to a mutation in the otoferlin gene and is expected to progress to clinical trials in 2021.

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To support the new research focus, Decibel is restructuring its employee base and discontinuing some early-stage discovery programs.

About Decibel Therapeutics, Inc.Decibel Therapeutics, a development-stage biotechnology company, has established the worlds first comprehensive drug discovery, development, and translational research platform for hearing loss and balance disorders. Decibel is advancing a portfolio of discovery-stage programs aimed at restoring hearing and balance function to further our vision of a world in which the benefits and joys of hearing are available to all. Decibels lead therapeutic candidate, DB-020, is being investigated for the prevention of ototoxicity associated with cisplatin chemotherapy. For more information about Decibel Therapeutics, please visit decibeltx.com or follow @DecibelTx.

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Contacts

Matthew Corcoran, Ten Bridge Communicationsmcorcoran@tenbridgecommunications.com (617) 866-7350

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Decibel Therapeutics Announces Strategic Research Focus on Regenerative Medicine for the Inner Ear - Yahoo Finance

Six patients with a rare blood disease are now in remission thanks to a new gene therapy. The condition, known as X-CGD, weakens the immune system leaving the body vulnerable to a range of nasty infections and shortens a persons lifespan. It is normally treated using bone marrow transplants, but matching donors to patients can be tricky and time-consuming and the procedure comes with risks.

A team led by UCLA recently treated nine people with the disease and six successfully went into remission, allowing them to stop other treatments. All six patients are doing well and havent suffered any adverse effects.

X-CGD is a form of chronic granulomatous disease (CGD). People with CGD have an inherited mutation in one of five genes involved in helping their immune system attack invading microbes with a burst of chemicals. This means that CGD sufferers have weaker immune systems than healthy people, so they have a greater risk of getting infections. These infections can be life-threatening, particularly if they affect the bones or cause abscesses in vital organs.

X-CGD is the most common type of CGD and only affects males. It is caused by a mutation in a gene on the X-chromosome. Current treatments are limited to targeting the actual infections with antibiotics as well as bone marrow transplants. Bone marrow contains stem cells that develop into white blood cells, so bone barrow from a healthy donor can provide a CGD patient with healthy white blood cells that can help their body to fend off disease.

However, bone marrow transplants are far from ideal. The patient has to be matched to a specific donor, and the body can reject the implanted bone marrow. That means that following a transplant, the patient needs to take anti-rejection drugs for at least six months.

For their new treatment, researchers removed blood cell-forming stem cells from the patients themselves and genetically modified them so that they no longer carried the unwanted mutation. Then, the edited stem cells were returned to their bodies, ready to produce healthy new infection-fighting white blood cells.

This is the first time this treatment has been used to try to correct X-CGD. The researchers followed up with the nine patients but sadly, two passed away within three months of the treatment. Its important to note that their deaths were not a result of the treatment but of rather severe infections that they had been suffering from for a long time. The remaining seven were followed for 12 to 36 months all remain free from infections related to their condition, and six have been able to stop taking preventative antibiotics entirely. The results are reported in Nature Medicine.

None of the patients had complications that you might normally see from donor cells and the results were as good as youd get from a donor transplant or better, said Dr Donald Kohn, a member of theEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLAand a senior author of the paper.

Whats more, four new patients have also been treated since the initial research was conducted. None experienced any adverse reactions and all remain infection-free. Now, the team plans to conduct a bigger clinical trial to further test the safety and efficacy of their new treatment, with the hopes that it may one day become available to the masses.

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New Gene Therapy Successfully Sends Six Patients With Rare Blood Disorder Into Remission - IFLScience

Chien-Shan Cheng, 1, 2,* Jing-Xian Chen, 3, 4,* Jian Tang, 1, 2 Ya-Wen Geng, 1, 2 Lan Zheng, 3, 4 Ling-Ling Lv, 3 Lian-Yu Chen, 1, 2 Zhen Chen 1, 2

1Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, Peoples Republic of China; 2Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, Peoples Republic of China; 3Department of Traditional Chinese Medicine, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai 200025, Peoples Republic of China; 4Workstation of Xia Xiang, National Master of Traditional Chinese Medicine, Department of Traditional Chinese Medicine, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai 200025, Peoples Republic of China

*These authors contributed equally to this work

Correspondence: Zhen Chen; Lian-Yu ChenDepartment of Integrated Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, Peoples Republic of ChinaTel +86-21-6417-5590 ext. 83628Email cz120@mail.sh.cn; lianyu_chen@hotmail.com

Purpose: Paeonol, a natural product derived from the root of Cynanchum paniculatum (Bunge) K. Schum and the root of Paeonia suffruticosa Andr. (Ranunculaceae) has attracted extensive attention for its anti-cancer proliferation effect in recent years. The present study examined the role of paeonol in suppressing migration and invasion in pancreatic cancer cells by inhibiting TGF- 1/Smad signaling.Methods: Cell viability was evaluated by MTT and colonial formation assay. Migration and invasion capabilities were examined by cell scratch-wound healing assay and the Boyden chamber invasion assay. Western Blot and qRT-PCR were used to measure the protein and RNA levels of vimentin, E-cadherin, N-cadherin, and TGF- 1/Smad signaling.Results: At non-cytotoxic dose, 100 &Mgr; and 150 &Mgr; of paeonol showed significant anti-migration and anti-invasion effects on Panc-1 and Capan-1 cells (p< 0.01). Paeonol inhibited epithelial-mesenchymal-transition by upregulating E-cadherin, and down regulating N-cadherin and vimentin expressions. Paeonol inhibited TGF- 1/Smad signaling pathway by downregulating TGF- 1, p-Smad2/Smad2 and p-Smad3/Smad3 expressions. Further, TGF- 1 attenuated the anti-migration and anti-invasion capacities of paeonol in Panc-1 and Capan-1 cells.Conclusion: These findings revealed that paeonol could suppress proliferation and inhibit migration and invasion in Panc-1 and Capan-1 cells by inhibiting the TGF- 1/Smad pathway and might be a promising novel anti-pancreatic cancer drug.

Keywords: paeonol, pancreatic adenocarcinoma, TGF- 1/Smad signaling, epithelial-mesenchymal-transition, Cynanchum paniculatum

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Paeonol Inhibits Pancreatic Cancer Cell Migration and Invasion Through | CMAR - Dove Medical Press

British scientists who announced last week their discovery of a new type of cancer-killing T-cell have entered a partnership with a biotechnology company pioneering the use of Dark Antigens to developT-cell receptor (TCR)-based immunotherapies and off-the-shelf cancer vaccines. The resultthey hopewill be a one-size-fits-all cancer therapy.

Last Monday, scientists at Cardiff University in the UK announced they had identified a new type of killer T-cella T-cell clonethat recognized and killed multiple different types of human cancer, while ignoring healthy, non-cancerous cells. The discovery, researchers said, offers hope of a universal cancer therapy. The researchers reported in Nature Immunology that these T-cells attacked many forms of cancer from all individuals. The T-cell clone killed lung, skin, blood, colon, breast, bone, prostate, ovarian, kidney and cervical cancer.

Less than a week later, the Cardiff researchers have announced they will enter a partnership with Ervaxx to eventually bring their discovery to patients.

Cardiff University Professor Andrew Sewell

The Cardiff University T-cell modulation group, within the Division of Infection and Immunity, studies all areas of T-cell biology including T-cell genetics, molecular biology, protein chemistry, crystallography and cell biology. The group aims to understand the genetic, biochemical and cellular mechanisms that govern T-cell responses in human diseases, such as HIV, EBV, tuberculosis autoimmunity and cancer.

Professor Andrew Sewell with Research Fellow Garry Dolton

Ervaxx is a UK biotechnology company based in London and Oxford, which is pioneering a new approach to developing targeted immunotherapies for treating and preventing cancer. These immunotherapies, including T-cell therapies, are based on new cancer targets (Dark Antigens) that derive from the dark matter of the genome, which are generally silenced in normal tissue but can become selectively activated in cancer.

T-cell therapies for cancer are the latest paradigm in cancer treatments. Current therapies include CAR-T and TCR-T, where immune cells are removed, genetically-modified and returned to a patients blood to seek and destroy cancer cells. Current therapies are personalized to each patient, target only a few types of blood cancer and have not been successful for solid tumors, which make up the vast majority of cancers.

In contrast, the newly discovered cell attaches to a molecule on cancer cells called MR1, which does not vary in humans.So not only would the treatment work for most types of cancer, said Professor Andrew Sewell, an expert in T-cells and a lead author on the study from Cardiff Universitys School of Medicine, but the same approach could be applied in all patients. It is hoped that the approach might eventually be applied as an almost instant off-the-shelf treatment.

The use of HLA-agnostic T-cell receptors has the promise to transform the treatment of common solid tumors that are presently incurable, said Carl June, MD, in reference to the Cardiff research. A leading expert in the delivery of successful T-cell therapies, June is a professor in Immunotherapy in the Department of Pathology and Laboratory Medicine and the director of the Center for Cellular Immunotherapies and of Translational Research in the Abramson Cancer Center of the University of Pennsylvania. As with organ or bone marrow transplants, previously identified cancer-specific T-cells have been suited only to small sections of the population who share specific tissue types, making it difficult to identify and treat the most appropriate patients. This new T-cell appears not to have these limitations, and if this is borne out in clinical testing, and the approach is shown to be safe and efficacious, it could represent a real advance for the field. We need to cure cancer and not turn it in to a chronic disease.

June studies various mechanisms of lymphocyte activation that relate to immune tolerance and adoptive immunotherapy for cancer and chronic infection. According to the Parker Institute, his research team published findings in 2011, which represented the first successful and sustained demonstration of the use of gene transfer therapy to treat cancer. Clinical trials utilizing this approach, in which patients are treated with genetically engineered versions of their own T-cells, are now underway for adults with chronic lymphocytic leukemia and adults and children with acute lymphoblastic leukemia. Early results in that group show that 90 percent of patients respond to the therapy, and more recently, trials of this approach have begun for patients with other blood cancers and solid tumors including pancreatic cancer, mesothelioma and the brain cancer glioblastoma. In 2017, it became the United States first FDA-approved personalized cellular therapy for the treatment of cancer.

Still, Sewell cautioned people from becoming overly optimistic too soon about Cardiffs findings. He said while the scientists discovery is potentially game-changing, an actual universal cancer therapy could be years away.I would really like to stress that we have not cured a patientour results were all laboratory based, albeit with patient T-cells and cancer cells. Clearing cancer in a culture dish and clearing it in a patient are two very different things.

When Cardiff researchers injected the new immune cells into mice with a human immune system and a human blood cancer line, the cancers cells were cleared to a level seen with CAR-T cells in the same mouse model, Sewell said. The group further demonstrated that equipping T-cells of skin cancer patients with the new receptor induced them to destroy not only the patients own cancer cells, but also other patients cancer cells in the laboratory, he said.

Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognizes and kills most human cancer types, while ignoring healthy cells, Cardiff reported in a press release. This TCR recognizes a molecule present on the surface of a wide range of cancer cells as well as in many of the bodys normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

Though there are various types of T-cells, Sewell said his interest is in killer T-cellsalso called cytotoxic T-cells. Killer T-cells are fascinating as they have the unique ability to see inside other body cells and scan them for anomalies he said. Conventionally, killer T-cells scan the molecular machines inside cells called proteins. A clever system presents bits of all the proteins inside each cell on its surface bound to molecular platforms called HLA [Human Leukocyte Antigen]. Normal, healthy body cells only present bits of normal proteins, and these are ignored by killer T-cells. If a cell is, for instance, infected with a virus, then it will contain some proteins of viral origin and bits of these will be displayed on the surface of the infected cell. Killer T-cells can recognize these protein fragments as foreign. This activates the killer T-cell to destroy the infected body cell and all its contents, including the virus. In this sense, killer T-cells act as a sophisticated seek and destroy weapon.

T-cells attacking cancer.

When cells become cancerous, they change the expression of some proteins and some proteins mutate, Sewell explained. These changes can also be detected by killer T-cells. Successful cancers go to great lengths to hide from killer T-cells, he said. We know that cancer often exploits the safety checkpoints that are built into T-cells to prevent them causing inflammation or autoimmunity. These checkpoints can be thought of as T-cell brakes, and successful cancers are often good at applying these brakes. Recent development of new drugs called checkpoint inhibitors prevents the application of these brakes and can result in complete clearance of some cancers in some people. Research that led to the discovery of checkpoint inhibitors was awarded the Nobel prize for Physiology or Medicine in 2018.

Sewell said the Cardiff teams discovery could mean exciting opportunities for pan-cancer, pan-population immunotherapies not previously thought possible. The research was funded by the Wellcome Trust, Health and Care Research Wales and Tenovus.

Until now, Sewell said, nobody knew this cell existed. He said the teams hypothesis is that the T-cell works by interacting with a molecule called MR1 which, in turn, flags up the distorted metabolism in a cancer cell.

Now that we know that these types of cells exist, we can actively look for others that work by a similar mechanism. Indeed, we have already found similar broadly tumoricidal, HLA-agnostic killer T-cells that see cancers via different surface molecules. The molecules targeted by these cells were also discovered using the CRISPR library approach. CRISPR gene editing has been a real game-changer.

Sewell said the next step will begin with safety testing on further healthy human cell lines in the laboratory. History has shown, he said, that some T-cells could attack things we dont want them to. We have already demonstrated that our new T-cell does not respond to 20 healthy cell types, he said. The human body has many more cell types than this so, as best we can, we need to rule out that this T-cell does not attack any further healthy human cell types. The new MR1-binding receptor has a natural sequence isolated from a healthy donor and thus the likelihood that it will attack healthy tissue is unlikely.

In any event, Sewell said it is important for people to acknowledge that this discovery has not been tested outside of the laboratory and not yet in human beings. It is impossible to reconstitute a whole human body as individual cell types in the laboratory, so after passing an accepted level of safety testing in this way, the next step is a first-in-man trial Sewell said. In order to minimize the risk, it is likely that the first time this type of T-cell is used in man, the T-cells will transiently [impermanently] express the relevant T-cell receptor and be given in low numbers, with escalation from there once safety is demonstrated. This way if there is any autoimmune attack it will be at low level and short-lived, so hopefully do minimal damage.

While Sewell hesitated at giving a timeline for when an actual universal cancer therapy or cure could be expected, he is hopeful that clinical trials may start in the next few years once further laboratory safety testing is completed.

The new collaboration to develop this recent discovery funded by Ervaxxwill support a multi-year research program with Sewells T-cell modulation group at Cardiff University focusing on the discovery and characterization of T-cells and TCRs reactive to cancer-specific antigens and ligands, including Ervaxx proprietary Dark Antigens.

The company has the right to advance resulting candidate T-cell/TCR-based immunotherapeutics and cancer vaccines through development and commercialization, Ervaxx stated in a press release.

Kevin Pojasek, Ervaxx CEO, said the collaboration with the Cardiff University research group shows early but enormous potential for the treatment of cancers. He said the partnership, which follows those with the University of Oxford, University of Cambridge and Johns Hopkins University School of Medicine, reinforces our ambition to collaborate with leading academic institutions and be at the cutting edge of the T-cell immunology field to drive the development of novel off-the-shelf cancer therapies.

In terms of the MR1 finding, when asked if it meant that some people are completely immune to cancer, Sewell said, Possibly. This immune cell could be quite rare, or it could be that lots of people have this receptor, but for some reason it is not activated. We just don't know yet, but we hope that this finding can be exploited and will pave the way for new cancer treatments.

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New Partnership Could Eventually Lead To One-Size-Fits-All Cancer Vaccines - Forbes

Precision medicine promises a new paradigm in oncology where every patient receives truly personalized treatment. This approach to disease diagnosis, treatment and prevention utilizes a holistic view of the patientfrom their genes and their environment to their lifestyleto make more accurate decisions.

Growing at a rate of 10.7 percent, the precision medicine market is expected to exceed $96 billion by 2024.1 Bioinformatics represent a significant share of the market, as bioinformatics tools enable the data mining necessary for rapid identification of new drug targets and repurposing of existing treatments for new indications.1 (Reuters) The oncology segment of the precision market is expected to experience an 11.1 percent compounded annual growth rate (CAGR) leading up to 2024 due to the success of recent targeted therapies and subsequent high demand.

Still, precision medicine is in its infancy, and making personalized treatment a reality for all patients requires a transformation in how novel therapies are developed and delivered. New regulatory, technical, clinical and economic frameworks are needed to ensure that the right patients are able to access the right therapy at the right time. In this article, we review the current state of precision medicine in oncology and explore some of the challenges that must be addressed for precision medicine to reach its full potential.

Great strides toward precision medicine are being made in the area of cancer immunotherapy, which is designed to boost a patients own immunity to combat tumor cells. The introduction of immune checkpoint inhibitors (PD-1/PD-L1 and CTLA-4 inhibitors) revolutionized treatment for certain hematologic malignancies and solid tumors. To date, immune checkpoint inhibitors have been approved by the U.S. Food and Drug Administration (FDA) for more than 15 cancer indications, but their widespread use has been hampered by unpredictable response rates and immune-related adverse events.

The approvals of the first chimeric antigen receptor (CAR)-T cell (CAR-T) therapies in 2017 were the next leap forward in precision medicine. These immunotherapies demonstrated that it was possible to take out a patients own T-cells, genetically modify them, and then put them back in to target cancer cells. With complete remission rates as high as 83 percent within three months of treatment, CAR-T therapies represent a seismic shift in our approach to cancer, bringing the elusive possibility of a cure one step closer. However, longer-term follow-up has shown that these remissions may not be durable2 and prevention of relapse must still be studied.

Ultimately, the goal of cancer immunotherapy is to stimulate the suppressed immune system of a patient with cancer so that it can launch a sustained attack against tumor cells.3 This is complicated, as the interactions between tumors and immune systemsometimes called the Cancer-Immunity Cycle (see Figure 1 in the slider above)4are complex and dynamic. The Cancer-Immunity Cycle manages the delicate balance between the immune systems ability to recognize non-self and the development of autoimmunity.

In some cases, the immune system may fail to recognize tumor cells as non-self and may develop a tolerance to them. Moreover, tumors have an armamentarium of methods for evading the immune system. Given this elaborate interplay between cancer and immunity, there is a wide range of potential cancer immunotherapy approaches:

The immune response to cancer involves a series of carefully regulated events that are optimally addressed as a group, rather than individually.4 The complexity of the immune response to cancer provides a strong rationale for combination therapies, for instance:

Increasingly, the development and deployment of immunotherapy relies on harnessing genomic data to identify the patients most likely to respond to immunotherapy and to customize immunotherapy for a given patient.6 Thus, molecular profiling technologies, such as next-generation sequencing, have become integral to drug development and patient selection. At the same time, researchers are focusing on identifying molecular alterations in tumors that may be linked to response.7 The molecular fingerprints of a tumor can be quite complex and heterogeneous, not only across tumors, but also within a single patient. Consequently, molecular tumor characterization requires both multidimensional data from laboratory and imaging tests and advanced software and computational methods for analyzing these data.8 This emergence of computational precision oncology is associated with both opportunities and challenges, from validation and translation to regulatory oversight and reimbursement.

The regulatory landscape is evolving to keep pace with technological advances in cell engineering and gene editing. Since 2013, the FDA has published four guidance documents on cellular and gene therapy products, as well as two guidance documents providing recommendations on regenerative medicine advanced therapies (RMATs). Specifically, their Expedited Programs for Regenerative Medicine Therapies for Serious Conditions, published in November 2017, provides guidance on the expedited development and review of regenerative medicine therapies for serious or life-threatening diseases and conditions. This document also provides information on the use of the accelerated approval pathway for therapies that have been granted the RMAT designation.9

In the EU, the European Medicines Agency (EMA) published a draft revision of its Guideline on quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells in July 2018.10 This draft revision includes current thinking on the requirements for nonclinical and clinical studies, as well as specific sections on the scientific principles and clinical aspects of CAR-T products.

Precision medicines such as CAR-T therapies require manufacturers to transform a complex, individualized treatment into a commercial product. In conventional manufacturing, the entire manufacturing process occurs within the confines of the manufacturing facility. With cell therapies, however, the process begins with the collection of cells from the patient and ends with administration of the final product (see Figure 2 in the slider above). In between, the cells are handed off multiple times for the process of genetic modification, creating a complex supply chain that blends manufacturing and administration.11

Moreover, in contrast to traditional manufacturing where the starting materials are standardized or well-defined, the starting materials for cell therapies are derived from patients and, thus, highly variable.

As evidenced by the manufacturing challenges that plagued the launch of Kymriah (tisagenlecleucel), even pharmaceutical giants have struggled with meeting label specifications for commercial use.13 To help address its manufacturing hurdles, Novartis acquired CellforCure, a contract development manufacturing organization, and plans to transform by focusing on data and digital technologies.14,15 What this means for sponsors is that robust, scalable manufacturing must be incorporated into clinical developing planning at its earliest stages.

The high price tags associated with CAR-T therapies illustrate how expensive targeted therapies are in comparison to their traditional counterparts.16 Existing health insurance models have not been structured to reimburse for costly treatments that offer the potential for long-term benefit or even cure. The pricing model for CAR-T therapies may be especially challenging for private insurance companies, which have higher turnover and shorter coverage windows than national health insurance programs. For sponsors of precision medicine therapies, one way to address the challenge of reimbursement is to create innovative, value- or outcomes-based pricing models, rather than focusing on sales volume. The success of these new pricing models will rely on patient selection. To demonstrate value and optimizing outcomes, sponsors will need to develop profiles of patients who are most likely to respond and provide tools for identifying these patients.8

Of note, on August 7, 2019, the Centers for Medicare & Medicaid Services (CMS) finalized the decision to cover FDA-approved CAR-T therapies when provided in healthcare facilities enrolled in the FDA risk evaluation and mitigation strategies (REMS) for FDA-approved indications. Medicare will also cover FDA-approved CAR-T treatments for off-label uses that are recommended by CMS-approved compendia.17

Beyond the pharmaceutical companies that are working to develop personalized treatments, the precision medicine ecosystem has a number of other key stakeholdersregulators, payers, diagnostic companies, healthcare technology companies, healthcare providers and, of course, patients. Pharmaceutical companies need to engage with each of these stakeholders by providing education or developing partnerships that help demonstrate the need for high-quality data collection, the value of precision medicine, and the process for identifying the right patients.

Sponsors may also benefit from engaging with patient advocacy groups as these groups play a critical role in connecting patients and caregivers with scientific and healthcare experts to learn about how new immunotherapy breakthroughs are changing the standard of care.

Empowered patients pushing for the latest innovations are propelling precision medicine forward, but we still have a way to go before the full potential of precision medicine is realized. In its maturity, precision medicine will not only enable the personalization of treatments for individual patients, but also inform public health at a population level as insights from the genetic and molecular data collected are used to advance our understanding of disease. Robust data collection and analysis, along with standardization, are required for building this foundation of precision medicine, and multi-stakeholder buy-in is necessary for addressing issues around data integration and privacy.

While significant challenges remain, the opportunity to transform patient outcomes and population health with precision medicine is tantalizing. Increasingly, we are seeing advanced technologiessuch as artificial intelligence and machine learningbeing incorporated into the drug discovery and development process. This underscores the critical need for a multidisciplinary approach to precision medicine, from discovery at the bench all the way through to delivery at the bedside, to help ensure that more patients can access the right therapy at the right time, and the right price.

References

Original post:
Realizing The Full Potential Of Precision Medicine In Oncology - Contract Pharma

Information is the stuff of life. Not limited to DNA, information is found in most biomolecules in living cells. Here are some recent developments.

Certain forms of sugars (polysaccharides called chitosans) trigger the immune system of plants. Biologists at the University of Mnster are deciphering the sugar code. They describe the variables in chitosans that constitute a signaling system.

Chitosans consist of chains of different lengths of a simple sugar called glucosamine. Some of these sugar molecules carry an acetic acid molecule, others do not. Chitosans therefore differ in three factors: the chain length and the number and distribution of acetic acid residues along the sugar chain. For about twenty years, chemists have been able to produce chitosans of different chain lengths and with different amounts of acetic acid residues, and biologists have then investigated their biological activities. [Emphasis added.]

These polysaccharides, also found in animals, are perhaps the most versatile and functioning biopolymers, the scientists say. If they can learn to decipher this complex code, they might find ways to protect plants without the use of pesticides.

DNA is becoming known as a more of a team member in a society of biomolecules. In some ways, it is more a patient than a doctor. It gets operated on by numerous machines that alter its message. One of the most important doctors that operates on RNA transcripts is the spliceosome, says a review article in The Scientist about alternative splicing. This complex molecular machine can multiply the messages in the coding regions of DNA by cutting out introns and stitching coded parts called exons together in different ways.

The process of alternative splicing, which had first been observed 26 years before the Human Genome Project was finished, allows a cell to generate different RNAs, and ultimately different proteins, from the same gene. Since its discovery, it has become clear that alternative splicing is common and that the phenomenon helps explain how limited numbers of genes can encode organisms of staggering complexity. While fewer than 40 percent of the genes in a fruit fly undergo alternative splicing, more than 90 percent of genes are alternatively spliced in humans.

Astoundingly, some genes can be alternatively spliced to generate up to 38,000 different transcript isoforms, and each of the proteins they produce has a unique function.

The discovery of splicing seemed bizarre from an evolutionary perspective, the authors say, recalling obsolete ideas about junk DNA. It seemed weird and wasteful that introns were being cut out of transcripts by the spliceosome. Then, the ENCODE project found that the vast majority of non-coding DNA was transcribed, giving these seemingly nonfunctional elements an essential role in gene expression, as evidence emerged over the next few years that there are sequences housed within introns that can help or hinder splicing activity.

This article is a good reminder that evolutionary assumptions hinder science. Once biochemists ridded themselves of the evolutionary notion of leftover junk in the genetic code, a race was on to understand the role of alternative splicing.

Understanding the story behind each protein in our bodies has turned out to be far more complex than reading our DNA. Although the basic splicing mechanism was uncovered more than 40 years ago, working out the interplay between splicing and physiology continues to fascinate us. We hope that advanced knowledge of how alternative splicing is regulated and the functional role of each protein isoform during development and disease will lay the groundwork for the success of future translational therapies.

Another discovery that is opening doors to research opportunities comes from the University of Chicago. Darwin-free, they announce a fundamental pathway likely to open up completely new directions of research and inquiry. Biologists knew about how methyl tags on RNA transcripts regulate the ways they are translated. Now, Professor Chuan He and colleagues have found that some RNAs, dubbed carRNAs, dont get translated at all. Instead, they controlled how DNA itself was stored and transcribed.

This has major implications in basic biology, He said. It directly affects gene transcriptions, and not just a few of them. It could induce global chromatin change and affects transcription of 6,000 genes in the cell line we studied.

Dr. He is excited about the breakthrough. The conceptual change in how RNA regulates DNA offers an enormous opportunity to guide medical treatments and promote health. Take a look at this design-friendly quote:

The human body is among the most complex pieces of machinery to exist. Every time you so much as scratch your nose, youre using more intricate engineering than any rocket ship or supercomputer ever designed. Its taken us centuries to deconstruct how this works, and each time someone discovers a new mechanism, a few more mysteries of human health make sense and new treatments become available.

Remember the evolutionary myth that jumping genes were parasites from our evolutionary past that learned how to evade the immune system? A discovery at the Washington University School of Medicine changes that tune, saying, Jumping genes help stabilize DNA folding patterns. These long-misunderstood genes thought by some evolutionists to be sources of novel genetic traits actually function to provide genomic stability.

Jumping genes bits of DNA that can move from one spot in the genome to another are well-known for increasing genetic diversity over the long course of evolution. Now, new research at Washington University School of Medicine in St. Louis indicates that such genes, also called transposable elements, play another, more surprising role: stabilizing the 3D folding patterns of the DNA molecule inside the cells nucleus.

It appears that by moving around, these genes can preserve the structure of DNA while not altering its function. (Note: the evolution they speak of appears to be microevolution, which is not controversial; hear Jonathan Wells discuss this on ID the Future.)

According to the researchers, this redundancy makes the genome more resilient. In providing both novelty and stability, jumping genes may help the mammalian genome strike a vital balance allowing animals the flexibility to adapt to a changing climate, for example, while preserving biological functions required for life.

Lead author Ting Wang says this gives insight into why coding regions between different animals vary in structure.

Our study changes how we interpret genetic variation in the noncoding regions of the DNA, Wang said. For example, large surveys of genomes from many people have identified a lot of variations in noncoding regions that dont seem to have any effect on gene regulation, which has been puzzling. But it makes more sense in light of our new understanding of transposable elements while the local sequence can change, but the function stays the same.

So while evolutionists had expected junk and simplicity, Wang says the opposite has occurred. We have uncovered another layer of complexity in the genome sequence that was not known before. Now, more discoveries are likely to flow from intelligent designs expectation that a closer look reveals more complexity.

In another recent podcast at ID the Future honoring the late Phillip E. Johnson, Paul Nelson likened a graph of mounting discoveries about life to a sharply rising mountain range. Darwin proposed his theory on the flatlands, unaware of the peaks his theory would have to explain. In the last fifty years, scientists have encountered mountain after mountain of complexity in life that evolutionary theory never anticipated back out there on the flatlands. We cant see the top of the mountains yet, but we know that were still not there, and we wont be for a long, long time, Nelson says. As we witness scientists continuing up the mountains, we anticipate with awe more wonders of design that will likely come to light in the next decade.

Image: Interior of a cell, courtesy of Illustra Media.

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Surprises in Cell Codes Reveal Information Goes Far Beyond DNA - Discovery Institute

GIOSTAR/HEAMGEN has developed and secured patented technology to manufacture lifesaving mature red blood cells from stem cells. The red blood cells are made utilizing a bioreactor that permits the production of mature red blood cells, under strictly controlled conditions, for transfusion therapy and replaces the need for a human blood donor. GIOSTAR/HEAMGEN mature red blood cells are safe and not compromised by inadequate pathogen detection and inactivation of diseases such as hepatitis C, HIV, hepatitis B and syphilis. The red blood cells are O-Negative (Universal Donor) to eliminate incompatibility and allosensitization reactions.

ATLANTA (PRWEB) January 29, 2020

GIOSTAR/HEAMGEN has developed and secured patented technology to manufacture lifesaving mature red blood cells from stem cells. The red blood cells are made utilizing a bioreactor that permits the production of mature red blood cells, under strictly controlled conditions, for transfusion therapy and replaces the need for a human blood donor. GIOSTAR/HEAMGEN mature red blood cells are safe and not compromised by inadequate pathogen detection and inactivation of diseases such as hepatitis C, HIV, hepatitis B and syphilis. The red blood cells are O-Negative (Universal Donor) to eliminate incompatibility and allosensitization reactions. Trauma situations often do not allow for adequate blood typing due to time restrictions, so the GIOSTAR/HEAMGEN red blood cells address that need effectively.

"There are three main problems for blood transfusions," stated Dr. Anand Srivastava, Founder and Chairman of GIOSTAR. "First we have to match the blood type. Second, there's not enough blood available every single time. And third, when we transfer blood from one person to another person, there is always a chance of the transfer of disease."

Watch a feature interview with Dr. Anand Srivastava on The DM Zone with host Dianemarie Collins.

The World Health Organization (WHO) published the first detailed analysis on the global supply and demand for blood in October 2019 and found that 119 out of 195 countries do NOT have enough blood in their blood banks to meet hospital needs. In those nations, which include every country in central, eastern, and western sub-Saharan Africa, Oceania (not including Australasia), and south Asia are missing roughly 102,359,632 units of blood, according to World Health Organization (WHO) goals. While total blood supply around the world was estimated to be around 272 million units, in 2017, demand reached 303 million units. That means the world was lacking 30 million units of blood, and in the 119 countries with insufficient supply, that shortfall reached 100 million units.

The global market opportunity for GIOSTAR/HEAMGEN technology presents not only a profitable and scalable business opportunity but also a significant social and environmental impact. The global market is estimated to be at least $ 85 Billion/year.

GIOSTAR/HEAMGEN has identified early entry global markets to include Military, Trauma, Asia (replace Hepatitis C contaminated blood products), Africa (AIDS contaminated blood), Newborns, Thalassemia patients, Allosensitized sickle cell disease patients. South Sudan was found to have the lowest supply of blood, at 46 units per 100,000 people. In fact, the country's need for blood was deemed 75 times greater than its supply. In India, which had the largest absolute shortage, there was a shortfall of nearly 41 million units, with demand outstripping supply by over 400 percent. Strategic investments are needed in many low-income and middle-income countries to expand national transfusion services and blood management systems. Oncology is a major user of blood transfusion but if countries don't have the capacity to manage the bulk of oncology, it will limit complex surgery options.

GIOSTAR/HEAMGEN has acquired the exclusive license to the patent for the technique for stem cell proliferation from University of California San Diego (UCSD). The founding team of GIOSTAR/HEAMGEN is comprised of the scientists and clinicians who were involved in creating the Intellectual Property at UCSD and has already achieved PROOF OF CONCEPT - the optimized lab scale proliferation of mature red blood cells - at UCSD as part of their research.

GIOSTAR/HEAMGEN is currently looking for strategic partnerships (Contact Doug@DMProductionsLLC.com) to accelerate the development of donor-independent red blood cells manufacturing capabilities and advance the proof of concept work already done (patented) around the manufacture of safe, universal donor, human red blood cells. GIOSTAR/HEAMGEN will also develop a full automated proprietary bioreactor using robotic technology to produce abundant quantities of red blood cells with a goal for cost-effective commercialization of fresh, human, universal donor Red Blood Cells (RBCs).

ABOUT GIOSTAR

Dr. Anand Srivastava is a Chairman and Cofounder of California based Global Institute of Stem Cell Therapy and Research (GIOSTAR) headquartered in San Diego, California, (U.S.A.). The company was formed with the vision to provide stem cell based therapy to aid those suffering from degenerative or genetic diseases around the world such as Parkinson's, Alzheimer's, Autism, Diabetes, Heart Disease, Stroke, Spinal Cord Injuries, Paralysis, Blood Related Diseases, Cancer and Burns. GIOSTAR is a leader in developing most advance stem cell based technology, supported by leading scientists with the pioneering publications in the area of stem cell biology. Company's primary focus is to discover and develop a cure for human diseases with the state of the art unique stem cell based therapies and products. The Regenerative Medicine provides promise for treatments of diseases previously regarded as incurable.

GIOSTAR is world's leading Stem cell research company involved with stem cell research work for over a decade. It is headed by Dr Anand Srivastava, who is a pioneer and a world-renowned authority in the field of Stem Cell Biology, Cancer and Gene therapy. Several governments and organizations including USA, India, China, Turkey, Kuwait, Thailand, Philippines, Bahamas, Saudi Arabia and many others seek his advice and guidance on drafting their strategic and national policy formulations and program directions in the area of stem cell research, development and its regulations. Under his creative leadership, a group of esteemed scientists and clinicians have developed and established Stem Cell Therapy for various types of autoimmune diseases and blood disorders, which are being offered to patients in USA and soon it will be offered on a regular clinical basis to the people around the globe.

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GIOSTAR Announces Medical Breakthrough in Biotechnology and Lifesciences To Manufacture Abundant, Safe Red Blood Cells From Stem Cells - Benzinga