Daily Archives: August 15, 2022

Should you find a link that does not work within any Guidance document, Rule or other document posted on the FDA Web site, please try searching for the document using the document title. If you need further assistance, please go to Contact FDA.

Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products; Draft Guidance for Industry3/2022

Human Gene Therapy Products Incorporating Human Genome Editing; Draft Guidance for Industry3/2022

Policy for Certain REMS Requirements During the Tocilizumab Shortage Related to the COVID-19 Public Health Emergency; Guidance for Industry and Health Care Professionals12/2021

Interpreting Sameness of Gene Therapy Products Under the Orphan Drug Regulations; Guidance for Industry9/2021

Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial; Draft Guidance for Industry9/2021

Manufacturing Considerations for Licensed and Investigational Cellular and Gene Therapy Products During COVID-19 Public Health Emergency; Guidance for Industry1/2021

Human Gene Therapy for Neurodegenerative Diseases; Draft Guidance for Industry1/2021

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry1/2020

Long Term Follow-up After Administration of Human Gene Therapy Products; Guidance for Industry1/2020

Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up; Guidance for Industry1/2020

Human Gene Therapy for Hemophilia; Guidance for Industry1/2020

Human Gene Therapy for Rare Diseases; Guidance for Industry1/2020

Human Gene Therapy for Retinal Disorders; Guidance for Industry1/2020

Evaluation of Devices Used with Regenerative Medicine Advanced Therapies;Guidance for Industry2/2019

Expedited Programs for Regenerative Medicine Therapies for Serious Conditions;Guidance for Industry2/2019

Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use; Guidance for Industry and Food and Drug Administration StaffUpdated: 12/2017

Same Surgical Procedure Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Guidance for Industry11/2017

Deviation Reporting for Human Cells, Tissues, and Cellular and Tissue-Based Products Regulated Solely Under Section 361 of the Public Health Service Act and 21 CFR Part 1271; Guidance for Industry9/2017

Recommendations for Microbial Vectors Used for Gene Therapy; Guidance for Industry9/2016

Design and Analysis of Shedding Studies for Virus or Bacteria-Based Gene Therapy and Oncolytic Products; Guidance for Industry8/2015

Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products; Guidance for Industry6/2015

Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products; Guidance for Industry3/2015

Guidance for Industry: BLA for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)

IND Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System - Guidance for Industry and FDA Staff3/2014. (This guidance finalizes the draft guidance of the same title dated June 2013.)

Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products(This guidance finalizes the draft guidance entitled Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products dated November 2012) 11/2013

Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage12/2011. (This guidance finalizes the draft guidance of the same title dated July 2007.)

Guidance for Industry: Clinical Considerations for Therapeutic Cancer Vaccines10/2011. (This guidance finalizes the draft guidance of the same title dated September 2009.)

Guidance for Industry: Potency Tests for Cellular and Gene Therapy Products1/2011. (This guidance finalizes the draft document of the same name, dated October 2008.)

Guidance for Industry: Cellular Therapy for Cardiac Disease(This guidance finalizes the draft guidance entitled Guidance for Industry: Somatic Cell Therapy for Cardiac Disease dated March 2009 (April 2, 2009, 74 FR 14992). 10/2010.

Guidance for Industry: Considerations for Allogeneic Pancreatic Islet Cell Products9/2009

Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)4/2008

Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products; Guidance for Industry8/2007

Guidance for Industry: Guidance for Human Somatic Cell Therapy and Gene Therapy3/1998

12/10/2021

More here:
Cellular & Gene Therapy Guidances | FDA

Failed efforts do not overshadow fields progress, resolve.

The recent news of Biogen and Ionis Pharmaceuticals ending a clinical trial for their amyotrophic lateral sclerosis drug candidate and Roches failed Phase III study in Huntingtons disease (HD) are hard to bear for many families holding on to hope in the face of devastating diseases with limited options. Their drug development journeys underscore the highly challenging nature of tackling rare diseases. As a geneticist, Ive seen firsthand the difficulties these patients endure. But even in the face of what might seem like failure, there is great progress. New thinking, research, and discoveries are only made possible by those who bravely forge new paths to gain a better understanding of the human body, even when that risk entails failure. Success will come.

The silver lining? Our strategy is sound. There is no doubt that genetic medicines work at addressing root causality in monogenic rare diseases like HD.

Back in the mid-1980s, a group of scientists came together at Alta Ski Resort to investigate whether it was possible to detect increased mutations in the survivors of the Hiroshima and Nagasaki bombings. The conclusion was that current methods were insufficient, yet the meeting spurred an energized response around genetic sequencing that resulted in the federal government funding the multibillion-dollar, multinational, and multiyear project to sequence all six billion letters of the diploid human genome, which resulted in the publication of the draft sequence of the human genome in 2001, years earlier than expected.

In less than four decades since, we have unraveled the blueprint of human life, cataloged the vast majority of mutations in the genetic code, implemented global infrastructure to provide rapid and inexpensive genetic testing to patients and physicians, and have a first wave of genetic medicines saving human lives. This is breathtaking progress.

However, there is still much work to do, with numerous challenges centered on improving the delivery, selectivity, and tolerability of these genetic medicines. We know the medicines work; it is just a matter of getting the therapy to the tissue where the disease manifests, dialing in the selectivity for the gene of interest, and engineering out toxicities.

With HD, patients receive an injection into the spinal cord, but in order for enough of a relatively large genetic medicine to penetrate into the deep brain structures to be effective, the high concentrations of the drug injected at the surface of the brain may result in neurotoxicity.

Rapid advancements in the areas of delivery, selectivity, and tolerability are happening. For delivery, innovations are allowing us to deliver genetic medicines across the blood-brain barrier to allow uniform exposures across all brain regions and not setting up toxic gradientswhich has been difficult for large molecules. This method avoids the brain surface toxicity. Since HD is a disease that involves the whole body, delivering a solution systemically via the bloodstream may address the whole-body manifestations of the disease. These new delivery devices are also noninvasive, using either ultrasound or emerging tech, and allow effective administration in a previously impossible manner.

For selectivity, emerging technologies can identify and engage with only the targeted mutated gene. Weve essentially reverse engineered nature so that the genetic-medicine-to-gene-target interface wont tolerate any mismatches. The treatment is viewed by the body as a complementary sequence to the mutant gene, yet one that contains a biologically inert chemistry that ensures no off-target engagement. The end result will be clean, highly effective, and well-tolerated medicines.

Because many of these therapies are delivered systemically, they can trigger an immune reaction that renders the medicine intolerable, yet even on this front, we are seeing advancements. By using the bodys own intelligent design, scientists have copied the existing framework and then improved upon it using synthetic strategies that allow for greater tolerance, thereby preventing the normally useful immune response from derailing healing.

We are in the most exciting time in the history of medicine, bar none. The science is dazzling. Patients should feel very optimistic. Cures are coming not in decades, but in a matter of years. The innovation thats happening today will be the breakthrough therapies of tomorrow. If you are looking for a silver lining, here it is.

Dietrich Stephan, CEO, Chairman, and Founder, NeuBase Therapeutics

See more here:
The Silver Lining Of Innovation in Genetic Medicine - Pharmaceutical Executive

The Center for Biologics Evaluation and Research (CBER) of the U.S. Food and Drug Administration (FDA) updated its Guidance Agenda in June 2022,1which provides that the agency plans to issue 18 guidance documents in 2022, including eight guidance documents on tissues and advanced therapies. In this alert, we highlight some key considerations from three draft guidance documents on human gene therapy products that incorporate gene editing (GE) components, chimeric antigen receptor (CAR) T cell products, and regenerative medicine therapies that can benefit biopharmaceutical developers and sponsors. Recognizing the challenges of developing such complex, multi-component biologic drug products, including unanticipated risks associated with on-target and off-target activities, these draft guidance documents describe the FDA's recommendations for preclinical and clinical testing, chemistry, manufacturing, and controls (CMC), as well as information that should be included in investigational new drug (IND) applications to ensure proper identity, potency/strength, quality, and purity of the investigational drug products. FDA recommends sponsors of such complex products to communicate with the Office of Tissues and Advanced Therapies (OTAT) in CBER early in product development before submission of an IND, to discuss the product-specific considerations in preparation for transitioning to the clinical phase.

FDA expects detailed information and data IND applications before sponsors can transition to clinical testing. We recommend biopharmaceutical developers and sponsors review the applicable FDA draft guidance documents early in their product development process to identify these needs. Work closely with both FDA regulatory counsel and intellectual property/patent counsel to ensure there is sufficient data to support an IND application, including adequate testing and quality control measures, and that CMC, preclinical, and clinical development plans are coordinated with intellectual property and patent strategies to ensure robust protection of their intellectual property and to maximize the benefits of their patents and FDA regulatory exclusivities. We also encourage interested persons to submit comments to shape the policies proposed in FDA's draft guidance documents prior to finalization.

Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing2

Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products3

Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies4

Stakeholders have until September 14, 2022, to submit comments to this draft guidance to ensure they are considered by FDA before finalization of the guidance.

For More Information

For questions regarding FDA strategy, approval, and regulatory compliance, please contact any member of Wilson Sonsini'sFDA regulatory, healthcare, and consumer productspractice. For questions regarding intellectual property and patent counseling, please contact any member of Wilson Sonsini'spatents and innovationspractice.

Andrea Chamblee,Paul Gadiock, andEva Yincontributed to the preparation of this Wilson Sonsini Alert.

[1] FDA, Guidance Agenda: Guidance Documents CBER is Planning to Publish During Calendar Year 2022 (Updated June 2022), available at https://www.fda.gov/media/120341/download.

[2] FDA, Draft Guidance for Industry: Human Gene Therapy Products Incorporating Genome Editing (March 2022), available at https://www.fda.gov/media/156894/download.

[3] FDA, Draft Guidance for Industry: Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, available at https://www.fda.gov/media/156896/download.

[4] FDA, Draft Guidance for Industry: Voluntary Consensus Standards Recognition Program for Regenerative Medicine Therapies (June 2022), available at https://www.fda.gov/media/159237/download.

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FDA Issues Draft Guidance to Facilitate Development of Human Gene Therapy, CAR T Cell, and Regenerative Medicine Products - Wilson Sonsini Goodrich...

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The family is cautiously optimistic about the improvements they are seeing in Michael, 4, since the gene therapy three months ago

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Doctors and researchers at The Hospital for Sick Children in Toronto have conducted one of the first individualized gene therapies as part of a single-patient clinical trial.

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There is hope that this success will begin to carve a path for precision child health care and more patients will have the opportunity to receive individualized care and treatments for a wide range of conditions.

David Malkin, lead of the Precision Child Health initiative, director of the Cancer Genetics Program, and the CIBC Childrens Foundation Chair in Child Health Research at SickKids, said the idea behind precision medicine is to use the unique features of an individual to make diagnosis more precise and to predict approaches and outcomes to treatments.

The concept is that we take all information, from the postal code to the genetic code, so it is more than medicine, its overall health and everything that encompasses, said Malkin.

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This groundbreaking individualized gene therapy procedure was years in the making.

After fundraising over $3.5 million to develop the therapy, successfully testing it in mice, and finally getting Health Canada approval, Toronto-born four-year-old Michael Pirovolakis received the procedure in March to hopefully slow the progression of his ultra-rare genetic condition, SPG50.

In April 2019, Michael was diagnosed with the progressive neurodegenerative disorder spastic paraplegia type 50 or SPG50. This condition, which is caused by variants in a gene called AP4M1, causes developmental delays, speech impairment, seizures, and progressive paralysis of the arms and legs. Over the course of a few years, children lose the ability to walk and use their hands, and eventually lose their mental capacity. It is also likely to be fatal.

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Michael is currently the only known patient with the condition in Canada. It is estimated that there are around 80 other children with SPG50 around the world, making it an ultra-rare disease.

Having a child with an ultra-rare disease is difficult, said Terry Pirovolakis, Michaels father. Someone has to be watching him at all times because he doesnt understand that climbing up on the couch or opening the fridge door could be unsafe.

We love him more than anything, you know, but it is difficult, he said.

Upon diagnosis, the treatment options for SPG50 were extremely limited. So, Terry and his wife Georgia started the charity CureSPG50 to raise money to develop a gene therapy that would help their son and others with SPG50.

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Gene therapies are usually used to treat conditions caused by genetic mutations, said Jim Dowling, staff physician in the Division of Neurology and senior scientist in the Genetics & Genome Biology program at SickKids.

The idea is that through some delivery mechanism, a gene is added back to an individual, he said.

Currently, the standard way of delivery is to replace the DNA of a virus, most commonly an adeno-associated virus (AAV), with the healthy DNA of the mutated gene. An AAV is used because people do not get sick when they are exposed to it, said Dowling.

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The virus is then given to the patient in a way that is specific to their condition. Sometimes this is through an IV, sometimes into the muscle, or even into the eyeball. For SPG50, gene therapy is given into the spinal fluid so it can easily access the brain.

There are risks associated with the gene therapy procedure, specifically if the patient may develop cancer.

It was exciting that we can give Michael a better life, but scary at the same time because the last thing I ever want to do is hurt my child, said Terry

What was especially unique about Michaels gene therapy was that it was designed specifically for him and his condition, said Dowling, who led Michaels clinical trial.

This type of individualized treatment is what the doctors behind the Precision Child Health initiative at SickKids have been working towards.

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Currently, the precision child health team is gathering case studies that show the use of individualized medicine, like Michaels gene therapy, to create a plan on how to go from the discovery of disease to medical intervention.

They hope that they will soon be able to give the same specialized treatment that Michael received to many more children with many different types of conditions.

Terry said that he and his family are cautiously optimistic about the improvements they are seeing in Michael since the gene therapy three months ago. He is doing well and there are small signs that his symptoms may be improving.

We wouldnt have gotten here without the amazing people helping us along the way, said Terry. I want to thank everybody for just truly being there for us.

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Michael will hopefully not be the only child that receives gene therapy to treat SPG50.

Currently, another batch of treatment is being made with the hope of having 10 doses to give to other kids, said Terry. If all goes to plan and the U.S. Food and Drug Administration (FDA) approves the treatment, in October there will be another clinical trial in Texas.

Terry said this plan relies on CureSPG50 raising another quarter of a million dollars per child. The money is needed to cover a five-year study and hospital costs.

Our goal is to save as many kids as we humanly can, said Terry. I hope we can raise enough money to eradicate this disease.

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Canadian family raised $3.5M to develop individualized gene therapy for son's rare condition - National Post

An Auburn University research team from the College of Veterinary Medicine and the College of Agriculture recently became the first to map a high-quality genome assembly of the blue catfish.

The genome, which was published in the journal GigaScience, is essential for genetic improvement using gene-editing or genome-assisted selection and will aid in the genetic enhancement of better catfish breeds for the multimillion-dollar catfish farming industry.

Catfish farming is the largest aquaculture industry in the U.S., accounting for approximately 70% of the nations total aquaculture output. Mississippi, Alabama, Arkansas and Texas account for the great majority of total U.S. freshwater catfish production, with Alabama ranking second only behind Mississippi. The primary fish utilized for farming purposes is a hybrid produced by breeding male blue catfish with female channel catfish.

The hybrid catfish is superior in growth and disease resistance, according to Xu Wang, assistant professor of comparative genomics in animal health in the College of Veterinary Medicines Department of Pathobiology and adjunct faculty investigator with the HudsonAlpha Institute for Biotechnology, who is one of the leaders of the project.

Faster growth means more profit. Originally, farmed fish were primarily channel catfish, but three major bacterial pathogens resulted in a 40% loss of production and annual economic damage of over $100 million in the U.S. industry alone. The hybrid mix of the blue and channel catfish has improved disease resistance and reduced mortality by half.

Even so, Wang says there is a critical need for further genetic improvement using genomic methods.

The channel catfish genome was mapped in 2016 by John Lius lab at Auburn [now at Syracuse University], but the blue catfish genome was not available until we published it, Wang added. Our high-quality blue catfish genome addresses the urgent needs to achieve the long-term goal of improving growth, feed utilization, stress and disease resistance and reproduction.

Wang served as senior author of the GigaScience paper, assisted by Haolong Wang (no relation), a doctoral student in biomedical sciences supported by both an Auburn Presidential Graduate Research Fellowship and a College of Veterinary Medicine Deans Fellowship. The veterinary researchers collaborated closely with a team from the College of Agricultures School of Fisheries, Aquaculture and Aquatic Sciences led by Professor Rex Dunham, an internationally recognized authority in the genetic enhancement and gene editing of catfish.

This is a fantastic step forward, Dunham said of the mapping of the blue catfish genome. There have been many genetic enhancement projects related to gene transfer and gene editing that were not possible for blue catfish without it. As a result, we could not do parallel work with what we are doing with channel catfish. Since a hybrid between channel and blue is the best genetic type for the catfish industry, that also put limitations on what we could do with these tools to improve the hybrid.

That roadblock is now gone. Having the blue catfish genome available opens a huge treasure chest of markers we can use for other approaches, such as marker assisted selection, and also gives us many more tools to distinguish and track different genetic types of blue catfish. Thanks to this research, we are much less limited than before.

Read more:
Auburn University researchers first to map blue catfish genome - Office of Communications and Marketing

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LAS VEGAS, Nevada (KVVU) -- A mysterious illness has turned one local familys life upside down. Their baby is fighting to survive after a rare diagnosis.

Josette Gentile told FOX5 her daughter Isla was a dream baby for the first few months of her life, but she became concerned when the infant wasnt able to hold her head up.

Her eyes just didnt focus like a usual baby does at four months old, Gentile shared.

That started months of testing. Doctors were stumped as to the diagnosis.

Every test kept coming back normal, just a little bit off but something was obviously wrong, recalled Gentile.

Things got worse, Isla was not eating and had no energy.

I took her to the ER. They did a bunch of tests and said everything was normal. Sent us home again and two days later Im like, I dont care what that doctor said, I know something is wrong with my baby. Took her to Summerlin Childrens Hospital where they took us very seriously and turns out she had a bladder infection that had turned to sepsis, Gentile explained.

Doctors said something was also wrong with her brain.

They life flighted us to Childrens Primary Hospital in Salt Lake City, said Gentile.

A team of doctors came together to solve the mystery: what was making Isla so sick?

One of her genes has two mutations. Its her FDXR gene. Only 35 people in the world have this mutation. Her specific mutation, the location in the gene and everything, she is the only one in the world known to have it, Gentile relayed.

The mitochondrial disease means Islas body cannot produce enough energy to function properly.

She has regressed to almost like a newborn, shared gentile.

Islas family, mom, dad Alejandro Ledesma, and 3-year-old sister Sage have dropped everything to focus on her care.

Its just flipped our lives completely upside down. This is our 21st day in the hospital, said Gentile.

There is no cure and no treatment. Doctors put Isla on a regimen of vitamins in hopes of boosting her energy.

What that is going to do is just make her more comfortable, her mother explained.

As the family is temporarily living in Salt Lake City, the Las Vegas community has stepped in to help. A fundraising page has raised thousands so far to help with their bills.

It has taken honestly a lot of stress off of us so we only have to worry about being here and keep her here as comfortably as we can, said Gentile.

It just makes you not feel alone in such a terrible time in your life, added Ledesma.

The disease will continue to get worse until Islas body can no longer handle it. The family plans to come back to Vegas if and when Isla is stable enough to travel.

Read more here:
Las Vegas baby diagnosed with rare genetic mutation - KVOA Tucson News

Imagine a patient with a rare genetic disorder that makes their arms and legs have imprecise and slow movements. For years, the patient has faced serious restrictions in day-to-day life. They tried several treatments, but all have failed to ease the symptoms.

Now imagine a university team discovering a therapy that could tackle this condition, with a solution that lies in the patients own body. The patients blood would be collected, some key cells would be separated in a laboratory, gene-editing techniques would be applied, and personalised medicine, produced with specialised equipment, would be injected back into the patients body.

A biological process would then be triggered in which all faulty genes would be corrected, reducing the diseases severity, perhaps correcting it all together. The modification would be restricted to the patient and would not be passed on to their children, since it would not affect reproductive cells.

Our story has a catch, though: the blood cells needed for the personalised medicine are very fragile and do not live very long outside the human body. This means theres little time to take the blood to the specialised laboratory, transport the cells to the production facility, and take the medicine back to the hospital where the patient is.

But what if all these production steps were quickly performed in the same place that is, in the hospital?

Read more: The human body has 37 trillion cells. If we can work out what they all do, the results could revolutionise healthcare

Our story is ceasing to be just imagination because this way of producing medicines in the hospital is actually emerging. Its what specialists call point-of-care manufacture. And there are several notable examples of it already in use.

For instance, a medicine for multiple myeloma (a type of bone marrow cancer) is being produced in the Hospital Clinic in Barcelona, Spain. Products for severe burns are being manufactured in Lausanne University Hospital in Switzerland.

At the University of Colorado in the US, researchers are developing a therapy for hard-to-treat lymphoma, a type of blood cancer. In the UK, an NHS Blood and Transplant laboratory is investigating the manufacture of red blood cells which, if successful, could be carried out in hospitals and other clinical settings for the treatment of cardiac diseases.

These illnesses might not have been treated if the medicines had needed to be frozen and transported over long distances, instead of being made in the hospital.

Given that these therapies have such a short shelf life and will need to be produced at the patients bedside, there are many things we need to consider before we can deploy them on a wider scale. For example, what measures should hospitals, companies, and regulators take to adopt this model and make it work? This is what our research team has been investigating.

Its vital that the same safe and high-quality production methods are used in different hospitals so that all patients receive the best possible care. This is why regulatory agencies in the UK are already proposing new ways of managing this model.

For example, it has been suggested that to begin with, manufacturers could oversee the medicines production in several different hospitals from a central site. They could also be responsible for providing training and quality control in the hospitals that have rolled out point-of-care manufacture to ensure that the products are safe and high-quality.

But just because a new policy has been made, doesnt mean it will be successfully implemented. This will mean hospitals and companies will need to change how they operate for these new technologies to be implemented safely and efficiently.

Our research, in collaboration with the Medicines and Healthcare Products Regulatory Agency (MHRA) and several public and private sector organisations has also looked at what benefits and challenges there may be in implementing this innovative approach to the production of medicines.

In a recent publication, we put forward several steps that need to be taken by regulators, hospital staff, and companies to make the production of personalised therapies in hospitals a reality. First, trusts, clinical centres and hospital staff will need to investigate how best to make therapy production happen in medical wards. They will also need to identify any issues such as staff training and data management which may stop this from happening.

Companies already developing these advanced treatments can also supply hospitals with manufacturing equipment and production system know-how, making it easier to start developing personalised therapies in hospitals with as little disruption to day-to-day operations as possible. Regulators may need to provide guidance for different therapies to ensure quality control and patient safety.

Now, let us return to our patients story. After receiving the therapy produced in the hospital, the patient goes on to live a healthy life and have a child that is diagnosed with the same genetic condition. But now, the way to receive treatment is much clearer.

The child will be treated in a specialised hospital where certified equipment and trained staff are available for producing and delivering an enhanced version of the personalised therapy. With more experience and better infrastructure in place, the child will receive a treatment that yields faster outcomes with fewer side effects.

But this will only be possible if everyone including hospital staff, manufacturers, scientists and policymakers work together to ensure point-of-care manufacture is successfully rolled out.

Excerpt from:
Personalised medicine made in hospitals can revolutionise the way diseases are treated the challenge now will be implementing it - The Conversation...

DNA replication and repair happens thousands of times a day in the human body and most of the time, people dont notice when things go wrong thanks to the work of Replication protein A (RPA), the guardian of the genome. Scientists previously believed this protein hero responsible for repairing damaged DNA in human cells worked alone, but a new study by Penn State College of Medicine researchers showed that RPA works with an ally called the WAS protein (WASp) to save the day and prevent potential cancers from developing.

August 9, 2022Penn State College of Medicine News

The researchers discovered these findings after observing that patients with Wiskott-Aldrich syndrome (WAS) a genetic disorder that causes a deficiency of WASp not only had suppressed immune system function, but in some cases, also developed cancer.

Dr. Yatin Vyas, professor and chair of the Department of Pediatrics at Penn State College of Medicine and pediatrician-in-chief at Penn State Health Childrens Hospital, conducted prior research which revealed that WASp functions within an apparatus that is designed to prevent cancer formation. As a result, some cancer patients had tumor cells with a WASp gene mutation. These observations led him to hypothesize that WASp might play a direct role in DNA damage repair.

Replication protein A (RPA) forms a complex with WASp at replication forks (red) within the nucleus (blue) of a human cell during DNA replication stress.

WAS is very rare less than 10 out of every 1 million boys has the condition, said Vyas, who is also the Childrens Miracle Network and Four Diamonds Endowed Chair. Knowing that children with WAS were developing cancers and also observing WASp mutations in tumor cells of cancer patients, we decided to investigate whether WASp plays a role in DNA replication and repair.

The researchers conducted protein-protein binding experiments with purified human WASp and RPA and discovered that WASp forms a complex with RPA. Further tests revealed that WASp directs RPA to the site where single DNA strands are broken and need to be repaired. According to Vyas, without the complex, DNA repair happens by secondary mechanisms, which can lead to cancer. This novel function of WASp is conserved through evolution, from yeast to humans. The results of the study were published in Nature Communications.

In the future, Vyas and colleagues will continue to study how their observations about this RPA-WASp complex formation can be applied to treating cancer patients. Vyas said it is possible that gene therapy or stem cell therapy could restore WASp function and may prevent further tumor growth and spread. He also mentioned the possibility of using WASp dysfunction as a biomarker for identifying patients at risk for autoimmune diseases and cancers.

This complex weve discovered plays a critical role in preventing the development of cancers during DNA replication, said Vyas. Translating this discovery from bench to bedside could mean that someday we have another tool for predicting and treating cancers and autoimmune diseases.

Seong-Su Han, Kuo-Kuang Wen of Penn State College of Medicine and formerly of the University of Iowa Stead Family Childrens Hospital; Mara Garca-Rubio and Andrs Aguilera of University of Seville-CSIC-University Pablo de Olavide; Marc Wold of University of Iowa Carver College of Medicine; and Wojciech Niedzwiedz of the Institute of Cancer Research also contributed to this research. The authors declare no conflicts of interest.

This research was supported in part by the National Institutes of Health, the ICR Intramural Grant and Cancer Research UK Programme, the European Research Council and the Spanish Ministry of Science and Innovation grant, the University of Iowa Dance Marathon research award, the Research Bridge Award from the Carver College of Medicine University of Iowa and endowments from the Mary Joy & Jerre Stead Foundation and from Four Diamonds and Childrens Miracle Network. The content is solely the responsibility of the authors and does not necessarily represent the official views of the study sponsors.

Read the full manuscript in Nature Communications.

If you're having trouble accessing this content, or would like it in another format, please email Penn State Health Marketing & Communications.

Link:
'Guardian of the Genome' and the 'WASp' team up to repair DNA damage - Penn State Health News

A yearslong effort by Novartis to repurpose a rare disease drug for cancer has come up short in a late-stage trial for a third time, closing off an opportunity for the Swiss pharmaceutical company to seek an expanded approval.

On Monday, Novartis revealedthe medicine, called canakinumab, failed to show a benefit versus placebo in a large Phase 3 study testing the drug in lung cancer patients following surgery to remove their tumors. Full results were not disclosed, but Novartis acknowledged the study did not meet its primary goal.

The outcome follows negative findings from two other Phase 3 lung cancer trials of canakinumab, which is sold as Ilaris for several fever syndromes and uncommon forms of arthritis.

Novartis quest to prove canakinumab might have broader potential was launched by a 10,000-person study called CANTOS, which in 2017 suggested treatment with the drug reduced heart risk as well as lowered the incidence and lethality of a common type of lung cancer.

The Food and Drug Administration in 2018 rejected Novartis pitch to secure canakinumabs approval as a treatment for reducing cardiovascular events like heart attacks and strokes. But the drugmaker pressed on in lung cancer, running a series of trials called CANOPY, the most recent of which was dubbed CANOPY-A.

We made an investment in the CANOPY program based on signals of reduced lung cancer incidence and mortality observed in the CANTOS study, said Jeff Legos, Novartis head of oncology and hematology development, in a statement.

While we are disappointed CANOPY-A did not show the benefit we hoped for, every trial generates scientific evidence that supports future research and development, he added.

CANOPY-A enrolled 1,382 patients with non-small cell lung cancer who had their tumor removed via surgery. Following their procedure, participants were randomized to receive either canakinumab or placebo and followed for several years.

However, treatment with Novartis drug did not extend disease-free survival, a metric designed to assess how long patients live without their disease returning. No unexpected safety signals were reported, according to Novartis, which will present its full findings at an upcoming medical meeting.

An antibody drug, canakinumab binds to a cytokine protein called IL-1. The protein helps control inflammatory signaling, and blocking it was thought to potentially suppress pro-tumor inflammation.

Novartis is still running one more trial of canakinumab in lung cancer, a Phase 2 study called CANOPY-N thats testing treatment before surgery rather than following it. Researchers at Memorial Sloan Kettering are running another study with Novartis assistance.

But CANOPY-A was Novartis clearest path to asking the FDA for an expanded approval in lung cancer and unlocking a market opportunity the company estimated could be worth between $1 billion and $2 billion in peak annual sales.

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Novartis bid to repurpose rare disease drug for cancer falls short in third trial - BioPharma Dive

Abnormal SOD1 protein detected in human spinal cord tissue (dark spots) Trist et al. 2022.

Normally, the protein superoxide dismutase 1 (SOD1) protects cells, but a mutation in its gene is thought to make the protein toxic; this toxic protein form is associated with hereditary forms of ALS. Abnormal mutant SOD1 is only found in regions of the spinal cord where nerve cells die, implicating this abnormal protein in cell death.

Previous investigations into the role of toxic forms of SOD1 protein largely focussed on mutant forms of the protein and were primarily conducted using animal and cellular models of ALS.

The study, led by a team from the University of Sydneys Brain and Mind Centre, advances our understanding of the causes of motor neurone disease by studying this abnormal protein in post-mortem tissues from patients with ALS.

We have shown for the first time that mechanisms of disease long hypothesised to occur in animal and cellular models are present in patients with motor neurone disease, says lead author Dr Benjamin Trist from the Brain and Mind Centre, Faculty of Medicine and Health.

This is a significant milestone in our understanding of ALS and motor neurone disease more broadly.

In related experiments, Professor Double and her team are also currently studying how abnormal SOD1 interacts with other disease-linked proteins in motor neurone disease. This work is in press and will be published in Acta Neuropathologica Communications.

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Abnormal protein could be a common link between all forms of motor neurone disease - University of Sydney