Category Archives: Genetic Therapy

Bioprocessing begins upstream, most often with culturing of animal or microbial cells in a range of vessel types (such as bags or stirred tanks) using different controlled feeding, aerating, and process strategies.

Beginning with harvest of material from a bioreactor, downstream processing removes or reduces contaminants to acceptable levels through several steps that typically include centrifugation, filtration, and/or chromatographic technologies.

Drug products combine active pharmaceutical ingredients with excipients in a final formulation for delivery to patients in liquid or lyophilized (freeze-dried) packaged forms with the latter requiring reconstitution in the clinical setting.

Many technologies are used to characterize biological products, manufacturing processes, and raw materials. The number of options and applications is growing every day with quality by design (QbD) giving impetus to this expansion.

Even as it matures, the biopharmaceutical industry is still a highly entrepreneurial one. Partnerships of many kinds from outsourcing to licensing agreements to consultancies help companies navigate this increasingly global business environment.

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Stability and Identity Testing: Cell and Gene Therapies - BioProcess Insider

PTC Therapeutics is a global biopharmaceutical company committed to the development of treatments for rare diseases where significant unmet medical needs exist.

Gene therapies are bringing hope to patients living with ultra-rare diseases. Unlike some medicines that treat the symptoms of a disease, gene therapy targets the root cause, with the potential to transform a disease with a single treatment or a short treatment course.(1) However, there is work to do to ensure patients can benefit from these novel treatments and to ensure an environment where R&D continues to evolve and flourish.

Working together with biopharmaceutical companies, regulators, payers, HTA bodies and policymakers, we have an opportunity to forge new ground so patients, caregivers and health systems can realize the full benefit of medical innovation. We are at the frontier of an exciting therapy pipeline.

To ensure success, we will need to work together to identify solutions in three key areas.

Getting the right diagnosis for rare diseases can be notoriously difficult. Including supporting increased access to genetic testing.(2) We often hear of families who have visited an endless number of specialists to find out why their child is not meeting expected developmental milestones. That is why we provide support across the entire patient journey, from disease awareness, physician education and early diagnosis initiatives. The inclusion of more diseases in newborn screening panels is a potential solution and an important component of any national rare disease action plan, as disease outcomes are often better if patients are treated early.(3) Newborn screening is mandated by law in some countries, but not all.(4)

In Europe, an example of best practice can be found in Italy, where diagnostic methods have been centralized in screening centres. Italys mandatory national program includes 40 disorders with 100% coverage.(5) However, the availability of newborn screening and the number of conditions screened varies considerably across Europe; for example in some countries, screening is only performed for 1 condition.(6) In the US, as a comparator, it is recommended that babies are screened for 34 core conditions and 26 secondary conditions.(7)

Regulatory and HTA frameworks were set up for the well-known therapy model, where treatment is given and paid for across a lifetime and often, to large numbers of patients. Gene therapies dont fit this model. Typically given only once, for a value that stretches over a lifetime. Whats more, these innovative therapies are genetically personalized, and for conditions that are so rare, there may only be a handful of affected patients in a country. The overall impact on the national healthcare budget may therefore be minimal. An evaluation must reflect these small patient numbers to encourage innovation. It is encouraging to see that in the UK NICE (National Institute for Health and Care Excellence), will work to improve how it considers real-world evidence from patients when evaluating new treatments.(8) This is incredibly important in rare diseases where large clinical trials are not possible.

There needs to be more significance given to data collected through close patient follow-up in disease and product registries that build up vital long-term safety and efficacy data. Inaddition, the process for gathering this data needs to be more consistent, coordinated and efficient.(9)

With very small patient populations, real-world evidence that is gathered is important in order to understand the long-term benefit of the treatment and the impact on the patientsquality of life.

The collaboration of biopharmaceutical companies, regulators, payers, HTA bodies and policymakers is important to design clear and uniform guidance so that real-world data isinter-changeable, interoperable and consistently accepted across Europe.Hopefully, this is an area the newly launched proposal from the European Commission on European Health Data Space can improve, in addition to the EMAs DARWIN project whichwill provide a network of real-world evidence across the EU.(10,11)

There are many new and innovative treatments, including gene therapies, that are being developed for patients living with rare diseases, providing hope for patients, many of whom are children with disabling and life-limiting conditions and who currently have few or no treatment options.(12) The potentially long-lasting effects of gene therapies will greatly reduce and in some cases eliminate the need for ongoing treatments over a patientslifetime. We need to work together to improve the regulatory and accesslandscape across Europe to ensure that these transformative and innovative therapies reach patients and at the same time continue to advance medical science in Europe.

1) Goswami R, et al. Gene Therapy Leaves a Vicious Cycle. Front Oncol. 2019;9:297.2) Marwaha S, et al. A guide for the diagnosis of rare and undiagnosed disease: beyond the exome. Genome Med. 2022;14(1):23.3) Kohlschtter A & van den Bussche H. [Early diagnosis of a rare disease in children through better communica-tion between parents, physicians and academic centers] Z Evid Fortbild Qual Gesundhwes. 2019;141-142:18-23.4) Loeber, JG. Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010. Int J Neonatal Screen. 2021;7(1):15.5) Sikonja J, et al. Towards Achieving Equity and Innovation in Newborn Screening across Europe. Int. J. Neonatal Screen. 2022, 8(2):31.6) Loeber JG. European Union Should Actively Stimulate and Harmonise Neonatal Screening Initiatives. Int J Neo-natal Screen. 2018;4(4): 32.7) National Conference of State Legislators (2017). State Newborn Health Screening Policies. Available at: https://www.ncsl.org/research/health/state-newborn-health-screening-policies.aspx (Accessed May 2022).8) NICE (2022) NICE publishes new combined methods and processes manual and topic selection manual for its health technology evaluation programmes Available at:https://www.nice.org.uk/news/article/nice-publishes-new-combined-methods-and-processes-manual-and-topic-selection-manual-for-its-health-technology-evaluation-programmes (Accessed May 2022).9) Kodra Y et al. Recommendations for Improving the Quality of Rare Disease Registries. Int. J. Environ. Res. Public Health 2018, 15(8):1644.10) European Commission. Questions and answers EU Health: European Health Data Space (EHDS). Available at: https://ec.europa.eu/commission/presscorner/detail/en/QANDA_22_2712 (Accessed May 2022).11) European Medicines Agency. Initiation of DARWIN EU Coordination Centre advances integration of real-world evidence into assessment of medicines in the EU. Available at:https://www.ema.europa.eu/en/news/initiation-darwin-eurcoordination-centre-advances-integration-real-world-evidence-assessment (Accessed May 2022).12) Bates M. Advances in Gene Therapy Offer Hope for Rare Disorders. IEEE Pulse 2019;10(6):9-12. EMEA Europe, Middle East and Africa, APAC Asia Pacific, R&D Research and Development, HTA Health Technology Assessment, EMA European Medicines Agency, EU Date of Preparation: September 2022 PTC/Corp/UK/22/0037.

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Preparing Europe for a new generation of innovative therapies - Open Access Government

9/22/2022

PITTSBURGH A collaborative group of neuroscientists from the University of Pittsburgh School of Medicine and Carnegie Mellon University received a $6.8 million grant from the National Institutes of Health (NIH) Brain Research Through Advancing Innovative Neurotechologies (BRAIN) Initiative to create an ultra-high resolution molecular atlas of the brain and develop brain cell type-specific strategies for effective and precise gene delivery.

The research will leverage genetic information resolved with single-cell precision to establish a comprehensive database of cell types and neural circuits comprising the brains cognitive and reward systems. In combination with ultra-high-resolution magnetic resonance imaging (MRI), the researchers intend to build brain atlases of marmosets and macaque monkeys and make them available to other neuroscientists across the world, free of charge.

This award enables cross-disciplinary collaboration between experts in neural imaging, gene therapy, machine learning, and molecular biology to advance our understanding of single-cell level organization of the brains essential systems, said project principal investigator William Stauffer, Ph.D., assistant professor of neurobiology at Pitt. We hope this unmatched degree of precision will eventually pave the way for the development of effective and precise gene editing technologies that might revolutionize treatment of previously fatal diseases, such as Alzheimers or Parkinsons.

The recently launched BioForge Initiative, backed by Pitt Senior Vice Chancellor for the Health Sciences, Anantha Shekhar, M.D., Ph.D., will be used to advance the wide-scale production and commercialization of the gene delivery vectors identified with the grant support.

We are excited that the services of a state-of-the-art biomanufacturing facility will soon be available in Pittsburgh to help make the lofty goal of delivering new and improved medical treatments for brain disorders a reality, said Shekhar. It feels very special to participate in a program that will not only bring life-saving treatments to our patients but also facilitate the dissemination of Pitt-developed technologies to research labs around the world and take a big step toward creating products with economic impact on the region.

The BRAIN Initiative was announced in 2013 to deepen understanding of the inner workings of the human mind and over the years has grown to prioritize the expansion of molecular cell-type profiling and data analysis, enabling genetic and non-genetic access to cell types across multiple species. The multi-year NIH grant was awarded as part of the Armamentarium for Precision Brain Cell Access, a large-scale NIH BRAIN Initiative project.

Delivery technologies for specific brain cell types are revolutionizing experimental neuroscience by allowing researchers to probe the cells and circuits underlying complex behaviors, said John Ngai, Ph.D., Director of the NIH BRAIN Initiative. An expanded toolkit of precision brain cell access tools supported by the first phase of the Armamentarium project could ultimately inform cell- and circuit-specific therapies for human patients, for example, those with epilepsy, neurodevelopmental diseases, or mood disorders.

Projects like the one led by Stauffer, who is interested in defining how different cell types contribute to behavior, as well as investigating cell type-specific disease processes, are essential to the Initiatives mission. Stauffer and his close collaborators, Leah Byrne, Ph.D., assistant professor of ophthalmology at Pitt, and Andreas Pfenning, Ph.D., assistant professor of computational biology at CMU, were awarded a BRAIN Initiative grant in 2018 to begin defining the molecular profiles of different neuron types.

Even a small piece of brain tissue contains dozens of different subtypes of neurons, each performing different functions during different behaviors, said Pfenning, who is a part of CMUs Neuroscience Institute. The ability to target these populations using viruses could accelerate basic research and also pave the way for targeted therapeutics.

Pfennings group will use custom-made machine learning models and evolutionary theory to identify sequences that are most likely to label subpopulations of neurons. His laboratory will also test the ability of those sequences to target specific cell types in the mouse brain.

Further building on the molecular profiling data, scientists at Pitts Brain Institute intend to identify cell type-specific drivers of gene expression in the forebrain and the frontal lobe and develop ready-to-use, specific and efficient gene delivery vectors, including adeno-associated viruses (AAVs). To develop novel AAVs, they will use scAAVengr, the single cell AAV engineering pipeline developed by Byrne. The team will combine scAAVengr-optimized AAV viral shells with newly identified cell type-specific enhancers, and the combination of these elements will generate viral vectors capable of delivering highly efficient and cell type-specific gene therapies. Afonso Silva, Ph.D., professor of neurobiology who holds an endowed chair in translational neuroimaging at Pitt and also a member of the Brain Institute, joins Stauffer, Byrne and Pfenning on the project team. The Silva lab will create an ultra-high resolution MRI atlas of the rhesus monkey brain. That MRI-based atlas will provide the framework for detailing how viral vector expression is controlled in a brain-wide fashion.

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Pittsburgh Project to Pave Way for Technology to Revolutionize Treatment of Fatal Brain Diseases - UPMC

All eyes are on the Emerald Isle this week as the Longevity Summit Dublin brings together a host of speakers covering the spectrum of this booming sector. Delegates have been hearing from some of the leading entrepreneurs, companies, investors, and researchers in the field as they address many of the hot-button topics affecting longevity. One of those speakers is the so-called father of genomics Harvard professor of genetics, George Church who closes the conference later today with a keynote on Gene, cell and organ therapies for de-aging.

Longevity.Technology: In addition to his Harvard professorship, Church heads up synthetic biology at the Wyss Institute, where he oversees development of new tools with applications in regenerative medicine. Much of his focus more recently has been on the development of gene therapies targeting age-related disease, a passion that led him to co-found Rejuvenate Bio, with the goal of creating full age reversal gene therapies. We caught up with Church ahead of his Dublin presentation for a brief conversation on longevity.

Dr Churchs name is synonymous with genomic science, and he was a key contributor to the Human Genome Project and technologies including next-generation fluorescent and nanopore sequencing, aimed at understanding genetic contributions to human disease. However, he doesnt feel that those initiatives did a huge amount to move the aging field forward.

They have provided aging researchers with useful reference points to go back and check their work, but the key advances in aging have really been made through the fundamental research on key pathways and drivers of aging, says Church. However, what we can take from those projects was their contribution towards technology improvements that have reduced the cost of DNA sequencing from three billion dollars in 2004 to just three hundred dollars today.

Thanks to technological advances, it was estimated that mapping a human genome cost an estimated $2025 million in 2006, although this was using haploid sequencing unsuitable for phenotype prediction. Skip ahead to today, and start-up Nebula Genomics (a company founded by Church) now offers diploid whole genome sequencing for as little as $300 a remarkable achievement by any standard. (Learn about the differences between haploid and diploid sequencing here.)

Alongside other technical developments, this kind of cost reduction will, Church believes, contribute to making gene therapies viable for everyone to benefit from, not just the wealthy. Public perception of gene therapy has taken a bashing recently thanks to drugs like Zynteglo, which was branded the most expensive medicine in history at $2.8 million per dose earlier this year. But Church doesnt see the same issue being a factor when it comes to future therapies against aging.

Those expensive gene therapies are for rare diseases, and their pricing reflects of the ratio of R&D costs to number of patients, says Church. But aging and its associated diseases affect nearly everyone. When you consider the volume of people that will be able to benefit from an age-reversing therapy, combined with the potentially huge benefits to society that such a treatment would enable, then it is a win-win for governments, healthcare providers and developers alike.

Under current conditions, gene therapies for aging and age-related diseases are likely to take 10 years to get approved, but Church points to how the world acted to fast-track approvals for COVID-19 vaccines in just one year.

The top five vaccines were formulated as gene therapies, and showed how quickly and safely we can move when there are extenuating circumstances, he says. Well, I would say that many more people are dying and in poor health as a result of the effects of aging, so perhaps aging should also be considered an extenuating circumstance.

In addition, Church points out, the cost of the vaccines was around $2 to $20 per dose a figure that healthcare systems around the world could manage if a gene therapy for aging were similarly priced.

So how close are we to seeing an approved gene therapy for aging? Pretty close, thinks Church, while admitting hes biased because of the work going on at Rejuvenate Bio. He co-founded the company in 2019 with his former postdoctoral fellow Noah Davidsohn, with the goal of eliminating aging and age-related diseases and increasing healthspan.

Church believes that gene therapies hold greater promise for age reversal than small molecules, because they might avoid frequent dosing and be more target-specific, while hitting all ten key pathways in one go, so its perhaps no surprise that Rejuvenate Bio is working on therapies that could tackle several age-related conditions at once.

We have already published on work conducted in mice, which showed that four age-related diseases (obesity, type II diabetes, heart failure, and renal failure) can be treated simultaneously with a single combination gene therapy, says Church. And weve gone on to show we can do it with five diseases as well.

But Rejuvenate Bio isnt stopping at mice. The company also has a significant animal health pipeline, which is already engaged in the development and commercialisation of a gene therapy for Mitral Valve Disease (MVD) in dogs.

Our animal health pipeline also gives us a unique advantage in that the results directly inform the direction of our work in our human therapies, and I believe this will allow us to deliver results faster.

The companys lead therapy (RJB-01) targets the FGF21 and sTGFR2 genes, and it is hoped it will deliver cardiovascular, metabolic and renal benefits. Following results from the trial in dogs, it is expected that RJB-01 will move into IND-enabling studies ahead of Phase 1 clinical trials likely next year.

Church is also enthusiastic about the recent uptick in investment and the growing interest in the longevity field.

Its clearly a good thing not only because it helps drive the field forward, but it also validates a lot of the great work that has been done in academia over the years, he says. Not that long ago, people were avoiding the field because of the sketchy image it had. Now we are attracting young, talented scientists, which is what we need to keep progressing.

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George Church: Learn from COVID and fast-track therapies that reverse aging - Longevity.Technology

ALDERLEY PARK, England--(BUSINESS WIRE)-- Charles River Laboratories International, Inc. (NYSE: CRL) and Cure AP-4, a non-profit foundation dedicated to raising funds and awareness about Adapter-Protein 4 Hereditary Spastic Paraplegia (AP-4 HSP), today announced a manufacturing collaboration. Charles River, a contract research and development manufacturing organization (CRO/CDMO), will provide High Quality (HQ) plasmid DNA for Cure AP-4s Phase I/II gene therapy trials against AP-4 HSP.

Founded in 2016 by the families of two newly diagnosed AP-4 HSP (SPG47) patients, Molly Duffy and Robbie Edwards, Cure AP-4s gene therapy treatment will look to address the root cause of AP-4 HSP, a rare neurodegenerative disorder, and is intended as a one-time, curative treatment for the patient.

What is AP-4 HSP? AP-4 HSP, also known as AP-4 Deficiency Syndrome, includes four sub-types of HSP: SPG47, SPG50, SPG51 and SPG52. Each of these HSP sub-types is associated with a defective autosomal recessive gene which causes a failure in the AP-4 Adaptor Complex. The phenotype and prognosis for each sub-type is extremely similar. Patients afflicted with any of the AP-4 HSP genetic disorders generally present with symptoms including global developmental delay, microcephaly, seizures, brain malformation, and hypotonia (low-muscle tone). The few patients who learn to walk independently tend to lose that ability a few months or few years later as they develop hypertonia (high-muscle tone) and muscle spasticity. Of the 249 currently confirmed global AP-4 HSP cases, most patients experience mobility in some or all extremities as the disorder progresses and are severely intellectually challenged.

Plasmid DNA Manufacturing Services The collaboration will leverage Charles Rivers market leading expertise in plasmid DNA production, specifically HQ plasmid, which combines key features of GMP manufacture with rapid turnaround times to accelerate the timeline to clinic. DNA plasmids are a critical starting material for many cell and gene therapy therapeutics and demand continues to outstrip supply. In response to this, Charles River recently announced the opening of a state-of-the-art HQ plasmid manufacturing center of excellence to address these supply shortages and support the growing needs of the cell and gene therapy field.

Charles River, with the acquisitions of Cognate BioServices, Cobra Biologics, and Vigene Biosciences in 2021, has extended its comprehensive cell and gene therapy portfolio to include CDMO capabilities spanning viral vector, plasmid DNA and cellular therapy production for clinical through to commercial supply.

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About Cure AP-4 Cure AP-4, originally known as Cure SPG47, was founded in 2016 by the families of two newly diagnosed SPG47 patients, Molly Duffy and Robbie Edwards. At the time there were only nine other documented cases worldwide, and due to the extreme rarity of the disorder there are no known treatments or cures.

About Charles River Charles River provides essential products and services to help pharmaceutical and biotechnology companies, government agencies and leading academic institutions around the globe accelerate their research and drug development efforts. Our dedicated employees are focused on providing clients with exactly what they need to improve and expedite the discovery, early-stage development and safe manufacture of new therapies for the patients who need them. To learn more about our unique portfolio and breadth of services, visit http://www.criver.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220906005064/en/

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Charles River and Cure AP-4 Announce Gene Therapy Manufacturing Collaboration - BioSpace

So far, Bcells havent gotten the same attentionindeed, genetically engineered versions have never been tested in a human. Thats partly because engineering B cells is not that easy, says Xin Luo, a professor at Virginia Tech who in 2009 demonstrated how to generate B cells that have an added gene.

That early work, carried out at Caltech, explored whether the cells could be directed to make antibodies against HIV, perhaps becoming a new form of vaccination.

While that idea didnt pan out, now biotech companies like Immusoft, Be Biopharma, and Walking Fish Therapeutics want to harness the cells as molecular factories to treat serious rare diseases. These cells are powerhouses for secreting protein, so thats something they want to take advantage of, says Luo.

Immusoft licensed the Caltech technology and got an early investment from Peter Thiels biotech fund, Breakout Labs. Company founder Matthew Scholz, a software developer, boldly predicted in 2015 that a trial could start immediately. However, the technology the company terms immune-system programming didnt turn out to be as straightforward as coding a computer.

Ainsworth says Immusoft had to first spend several years working out reliable ways to add genes to B cells. Instead of using viruses or gene editing to make genetic changes, the company now employs a transposona molecule that likes to cut and paste DNA segments.

It also took time to convince the FDA to allow the trial. Thats because its known that if added DNA ends up near cancer-promoting genes, it can sometimes turn them on.

The FDA is concerned if you are doing this in a B cell, could you develop a leukemia situation? That is something that they are going to watch pretty closely, says Paul Orchard, the doctor at the University of Minnesota who will be recruiting patients and carrying out the study.

The first human test could resolve some open questions about the technology. One is whether the enhanced cells will take up long-term residence inside peoples bone marrow, where B cells typically live. In theory, the cells could survive decadeseven the entire life of the patient. Another question is whether theyll make enough of the missing enzyme to help stall MPS, which is a progressive disease.

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A new gene therapy based on antibody cells is about to be tested in humans - MIT Technology Review