Category Archives: Gene therapy

Avrobio has shared data on the first Gaucher disease patient to receive its gene therapy AVR-RD-02. The patient, who was stable on enzyme replacement therapy at baseline, experienced a 22% drop in a toxic metabolite after receiving AVR-RD-02 and stopping taking the standard of care.

Gaucher, like the Fabry disease targeted by Avrobios lead prospect, is currently treated using enzyme replacement therapies sold by Sanofi and Takeda, which entered the market through its takeover of Shire. However, a significant minority of patients experience physical limitations despite treatment. Negative outcomes include bone pain and spleen enlargement. Johnson & Johnsons Zavesca offers an oral alternative, but there remain unmet medical needs.

Avrobio is developing AVR-RD-02 to address those needs. The data shared as part of Avrobios R&D day mark the start of the effort to show AVR-RD-02 performs as hoped in the clinic.

The first patient to receive AVR-RD-02 discontinued enzyme replacement therapy one month before taking the gene therapy. Three months after receiving the gene therapy, levels of Gaucher biomarker lyso-Gb1 had fallen 22%. The patients level of plasma chitotriosidase, a biomarker of cells associated with severe organ damage, was down 17%. Hemoglobin and platelets were in the normal range.

AVR-RD-02 triggered those changes without causing serious adverse events. The data drop offers an early indication that Avrobio may be able to improve outcomes by harvesting hematopoietic stem cells, adding a gene that encodes for glucocerebrosidase and reinfusing the cells back into the same patient. With enzyme replacement therapies costing healthcare systems up to $400,000 a year per patient, there is scope for AVR-RD-02 to cut the cost of treating Gaucher disease.

Avrobio shared the early look at clinical data on AVR-RD-02 alongside updates about other assets. There is now more than three years of data on some Fabry patients treated with Avrobios lead asset, putting the company in a position to plot a path to accelerated approval. Avrobio plans to submit its briefing book to the FDA by the end of the year to align on an accelerated approval strategy.

The update also covered cystinosis candidate AVR-RD-04. The first patient to receive the candidate is off oral and eye drop cysteamine 12 months after receiving the gene therapy. The number of crystals in the patients skin are down 56%, leading Avrobio to posit they may have gained the ability to make their own functional cystinosin protein.

See more here:
Avrobio tracks improvements in first patient treated with Gaucher gene therapy - FierceBiotech

NEW YORK, Nov. 18, 2020 (GLOBE NEWSWIRE) -- Prevail Therapeutics Inc. (Nasdaq: PRVL), a biotechnology company developing potentially disease-modifying AAV-based gene therapies for patients with neurodegenerative diseases, today announced that the United States Patent and Trademark Office (USPTO) onNovember 17, 2020issued a composition of matter patent, U.S. Patent No. 10,837,028,with claims directed to the AAV vector used in PR001, Prevails experimental gene therapy program for the treatment of Parkinsons disease with GBA1 mutations (PD-GBA) and neuronopathic Gaucher disease (nGD). The base patent term extends until October 3, 2038, excluding patent term extensions or coverage in additional related patent filings.

We are excited to make important progress this year with PR001, which is being evaluated in the Phase 1/2 PROPEL trial for patients with Parkinsons disease with GBA1 mutations and in the Phase 1/2 PROVIDE trial for patients with Type 2 Gaucher disease, said Asa Abeliovich, M.D., Ph.D., Founder and Chief Executive Officer of Prevail. We are advancing clinical development of PR001 to make a potentially transformative difference for these patients who currently have no approved treatment options.

The Company recently announced that patient dosing has continued in the Phase 1/2 PROPEL clinical trial of PR001 for PD-GBA patients, and it expects to provide the next biomarker and safety analysis on a subset of patients in the PROPEL trial by mid-2021. The Company expects to initiate enrollment of the Phase 1/2 PROVIDE clinical trial of PR001 for Type 2 Gaucher disease patients in the fourth quarter of 2020 and currently anticipates it will provide the next update on PR001 biomarker and safety data for nGD in 2021.

The U.S. Food and Drug Administration has granted Fast Track designations for PR001 for the treatment of PD-GBA and nGD. In addition, the FDA granted PR001 Rare Pediatric Diseasedesignation for the treatment of nGD, and Orphan Drugdesignation for the treatment of patients with Gaucher disease.

About Prevail TherapeuticsPrevail is a gene therapy company leveraging breakthroughs in human genetics with the goal of developing and commercializing disease-modifying AAV-based gene therapies for patients with neurodegenerative diseases. The Company is developing PR001 for patients with Parkinsons disease with GBA1mutations (PD-GBA) and neuronopathic Gaucher disease (nGD); PR006 for patients with frontotemporal dementia withGRNmutations (FTD-GRN); and PR004 for patients with certain synucleinopathies.

Prevail was founded by Dr.Asa Abeliovichin 2017, through a collaborative effort withThe Silverstein Foundationfor Parkinsons with GBA and OrbiMed, and is headquartered inNewYork, NY.

Forward-Looking Statements Related to PrevailStatements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Examples of these forward-looking statements include statements concerning the potential for Prevails gene therapy candidates to make a transformative difference for patients with neurodegenerative diseases; the expected timing of reporting additional interim data on a subset of patients from the PROPEL trial; and the anticipated timing of enrollment of and the next update on data from the PROVIDE trial. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. These risks and uncertainties include, among others: Prevails novel approach to gene therapy makes it difficult to predict the time, cost and potential success of product candidate development or regulatory approval; Prevails gene therapy programs may not meet safety and efficacy levels needed to support ongoing clinical development or regulatory approval; the regulatory landscape for gene therapy is rigorous, complex, uncertain and subject to change; the fact that gene therapies are novel, complex and difficult to manufacture; and risks relating to the impact on our business of the COVID-19 pandemic or similar public health crises. These and other risks are described more fully in Prevails filings with the Securities and Exchange Commission (SEC), including the Risk Factors sections of the Companys most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the SEC, and its other documents subsequently filed with or furnished to the SEC. All forward-looking statements contained in this press release speak only as of the date on which they were made. Except to the extent required by law, Prevail undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Media Contact:Lisa QuTen Bridge Communications LQu@tenbridgecommunications.com678-662-9166

Investor Contact:investors@prevailtherapeutics.com

Read more:
Prevail Therapeutics Granted Composition of Matter Patent for Experimental Gene Therapy Program PR001 - GlobeNewswire

Maryland, US headquartered company, Orgenesis, is championing a model that aims to bring down those costs it works with partner hospitals throughout the commercialization process.

The companys CGT platform, consisting of a pipeline of licensed cell and gene therapies, scientific expertise, customised processing systems, and an ecosystem of healthcare providers and research institutes, is designed to provide a pathway for groundbreaking autologous therapies to become commercially available on an industrial scale and at prices accessible to large populations.

Orgenesis business model is one focused on decentralization, enabling precision medicines to be prepared on-site at hospitals. In this way, we can really expedite cell and gene therapy development, said Orgenesis CEO, Vered Caplan.

With operations in the US, Europe, Israel and South Korea, Orgenesis has now created an international network of point of care (POCare) centers to serve patients directly in the hospital setting.

Beyond the US, we have POCare centers in many countries in Europe such as Greece, the Netherlands, Belgium, Slovenia, Italy and Spain; we also have centers in Israel, in Korea and in India and we will be starting up soon in Dubai,said the CEO.

The goal is to make gene and cell therapies feasible for large numbers of patients, said Caplan. We used to work as a contract development and manufacturing organization (CDMO) but we sold that business to Catalent at the beginning of the year.

The centralized processing and supply chain model only served to create a frustrating working environment, with plenty of constraints, said the Orgenesis lead.

We realized very quickly that we couldnt really ramp up to large scale relying on that kind of centralized model, particularly for autologous products, which represent most of the market today. It takes six months to train someone to work in a high-grade cleanroom there is a lot of work and expense involved in that and there is a limited number of patients that can be treated in such cleanrooms the utilization rate is very low - it [centralized processing and supply] is a very inefficient and costly way to supply and to develop medicine there is so much manual work involved, she told BioPharma-Reporter.

The company had been working for a number of years, investing a huge amount of effort in developing a range of automation solutions to supplant those manual processes, as well as building its mobile CGT processing labs and units (OMPULs), she said.

We had been fielding so many requests from hospitals that wanted to collaborate with us, asking us to make or scale up their CAR-T and other therapies. We realized that in order to get this done, we needed to take a decentralized approach and that we needed to provide a solution, not only for one hospital, but for every hospital that wanted these type of therapies; and we saw that such a model brings down the price of the therapy tremendously.

A hospital gives Orgenesis a license to work on the therapy, on the processing; production of the final product is automated and supplied via an on-site point-of-care processing unit. Orgenesis then sets about democratizing the treatment,making it available to any hospital in its POCare network.

The company says the final customized, automated processing system it has developed, with the integrated specific therapy, solves a variety of processing and cost hurdles. It results in a lower required grade of cleanroom, it simplifies facility management requirements, it enables multi-batch processing per cleanroom, which means reduced technical staffing. Moreover, the localized processing eliminates the many logistical difficulties associated with traditional, centralized manufacturing and transport.

Overall, it is said to provide faster turnaround, increased safety, and improved quality control management on-site.

Hospitals really want to supply CGTs, while patients are reading about such treatments and making inquiries of healthcare providers, she added.

Ours is really a combined licensing and service model.

We are like Uber. If you have a car, you want to make some extra revenue, you call up Uber and it gives you the network, the technology and all the operating procedures to be a taxi driver. That is very much what we do in terms of hospitals we give them the ability to be biotech companies, because this is not the standard thing they do, they dont want to take responsibility for cell and gene therapy it is too much for them. They want to treat patients, but they want to have that local supply, so we give them the technology and the capabilities to do that. We give them regulatory support for clinical trials, we give them CRO support, we give them a network - so they can function and do what they need to do, which is to undertake research and treat patients.

Orgenesis intends to leverage its network of regional partners to advance the development and commercialization of its therapeutic pipeline. Towards this end, it said its partners have committed to funding the clinical programs. In turn, the company typically grants its partners geographic rights in exchange for future royalties, and a partnership with Orgenesis to support the supply of the targeted therapies. Through this model, Orgenesis has already signed contracts, which it expect to generate over US$40M in revenue over the next three years, if fully realized.

On the therapeutic front, Orgenesis is focused on several key verticals, including immuno-oncology, anti-viral, and metabolic/auto-immune diseases.

It recently acquired Koligo Therapeutics, with the aim of leveraging Koligos 3D-V bioprinting technology across its POCare Platform. That technology, which utilizes 3D bioprinting and vascularization with autologous cells to create biodegradable and shelf-stable three-dimensional cell and tissue implants, is being developed for diabetes and pancreatitis, with longer term applications for neural, liver, and other cell/tissue transplants.

In February this year, Orgenesis announced that it has entered into a collaboration agreement with the John Hopkins University to utilize the POCare platform to develop and supply a variety of CGTs including cell-based immunotherapy technologies.

And the University of California, Davis (UC Davis) joined its POCare network in January. The collaboration will involve the scale up and integration of UC Davis lentiviral vector process.

Today we are very much in validation mode. Most of the therapies in this space, and the ones we have licensed from the hospitals I think we have about 25 today are all at different stages of clinical development. Some have been used to treat patients but that has all been done under hospital exception.

When we adopt a therapy into the network, we run it through the entire R&D, formal clinical and regulatory processes as [our goal] is a harmonized process, to have the same standard [in our closed systems] at our [POCare] centers, whether that is in Germany or Korea, said the CEO.

The rest is here:
Orgenesis CEO talks disruption: 'We are the Uber of the cell and gene therapy space' - BioPharma-Reporter.com

Catalent has appointed Behzad Mahdavi, Ph.D., MBA, as Vice President of Open Innovation, Biologics, Cell and Gene Therapy. In this new role, Dr. Mahdavi will join a team of experts in Catalents Science and Technology Group that works with customers and external innovators in both small and large molecules, to accelerate the adoption of new development and drug delivery technologies, and scalable manufacturing processes and techniques. He reports to Julien Meissonnier, Catalents Chief Scientific Officer.

Dr. Mahdavi has more than 20 years of experience in developing and implementing growth strategies in the biopharmaceutical industries. Dr. Mahdavi joins Catalent after a 13-year career at Lonza, where he held the role of Vice President Strategic Innovation & Alliances, and various board-level positions at other innovative companies. Prior to joining Lonza, he was Chief Executive Officer of SAM Electron Technologies.

As a company, Catalent continues to invest in the rapidly evolving and growing areas of cell and gene therapies and next-generation biopharmaceuticals, which are redefining the landscape of treating diseases, commented Mr. Meissonnier. I am delighted to welcome Behzad to Catalent, as he brings significant experience in leveraging accelerated innovation with strategic external sourcing, to further strengthen our strategy of delivering the therapies of tomorrow to patients faster, and more efficiently.

Originally posted here:
Catalent Appoints Open Innovation, Biologics, Cell And Gene Therapy VP - Contract Pharma

Vivet Therapeutics and Pfizer are one step closer to bringing a gene therapy for a rare liver disorder into the clinic.

The companies announced Wednesday morning that the FDA has accepted its IND application for a Phase I/II study in the treatment of Wilsons disease. The study, evaluating a program dubbed VTX-801, is expected to launch early next year.

VTX-801 is an rAAV-based gene therapy vector designed to deliver a protein called ATP7B in the hopes of restoring copper homeostasis, reversing liver pathology and reducing copper accumulation in the brain, as it was shown to do in mouse models.

The study will be open label and not be randomized. Researchers will give a one-time IV infusion of the gene therapy in up to 16 adult patients, with the goal of evaluating three different dosage levels. Ultimately, the companies set a primary endpoint for safety and tolerability after 52 weeks.

In March 2019, Pfizer acquired a minority stake in the company, and in September, the big pharma agreed to manufacture the VTX-801 vector for this Phase I/II study. Max Gelman

Florida-based biotech Generex has inked the biggest deal (it) could even imagine, bagging $50 million from a consortium of Chinese institutions that licensed its Ii-Key vaccine tech for infectious diseases and cancer.

Comprising hybrid peptides and a suppression, the platform has spawned a vaccine candidate against SARS-CoV-2 in addition to a pipeline of immuno-oncology therapies.

We are able to generate a detailed immune activation profile of our Ii-Key vaccine candidates by screening blood samples from COVID-19 recovered patients, explained Richard Purcell, EVP of R&D.

In addition to the upfront fee for the overall deal, the unnamed partners have handed over $5 million to license the Covid-19 vaccine candidate and promised a $20 million success fee if its approved in China. Separate contracts for the other indications are being finalized. Amber Tong

Read more:
News briefing: Pfizer and Vivet get the OK to start gene therapy trial for rare liver disorder; Florida biotech inks $50M China deal - Endpoints News

By taking advantage of a natural process of gene silencing, a new gene therapy approach appears to prevent the toxicity todorsal root ganglion(DRG) a specific cluster of sensory neurons seen in non-human primates during gene therapy studies for neurological disorders, researchers report.

The approach successfully protected the primates DRG from excessive activity of the introduced gene known as a transgene and subsequent toxicity, without affecting the transgenes activity elsewhere in the nervous system.

DRG inflammation and toxicity was observed in non-human primates after spinal canal injection of AVXS-101 approved asZolgensma when given as an intravenous infusion prompting a partial hold of a Phase 1/2 trial (NCT03381729) to allow for further investigation.

That trial, calledSTRONG, is testing intrathecal (spinal canal) injection of this gene therapy in children with spinal muscular atrophy (SMA) between 6 months and 5 years old.

The study, MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates, was published in the journal Science Translational Medicine.

We believe that this new approach could improve safety in genetherapyuniversally, as well as in SMA, Juliette Hordeaux, PhD, the studys first author at University of Pennsylvanias Perelman School of Medicine (Penn Medicine) said in a press release.

This approach could be used to design other gene therapy [carriers] to repress transgene [activity] in the cell types that are affected by the toxicity and not others, which is critical, because you need [such activity] everywhere else to effectively treat the disorder, added Hordeaux, who is also senior director of translational research for Penn Medicines gene therapy program.

Gene therapy works to deliver a functional version of a gene to correct or replace a faulty gene within specific cells in the body. Most therapy approaches today use a modified and harmlessadeno-associated virus(AAV) as a carrier for the working gene, a vehicle to transport it to a target cell.

But previous studies, including primate work by Penn researchers, showed that AAV-based gene therapies targeting the central nervous system (CNS; brain and spinal cord) can damage the DRG, a cluster of neurons of the spinal nerve that bring sensory information from the periphery to the spinal cord.

Notably, DRG toxicity was observed in studies regardless of the therapys route of administration (directly into the bloodstream or into the spinal canal). No reports of such toxicity in humans, including children treated in STRONG, are known.

Conventional immunosuppressive regimens were ineffective in preventing this toxicity, strongly indicating that an excessive immune response was not its cause. This led Hordeaux and her Penn colleagues to evaluate whether the damage was related to excessive levels of the transgenes product, which could cause cellular stress.

To test their idea, they took advantage of RNAi, a natural process of gene silencing, in which microRNA (miR) molecules bind to a specific messenger RNA (mRNA), targeting it for destruction and preventing the production of that protein. (mRNA is the molecule derived from DNA and used as a template for protein production.)

Since the miR183 complex is specifically produced in sensory tissues and organs such as dorsal root ganglion, the researchers introduced miR183s sequence targets at the endof the transgene sequence in an AVV. With this, any mRNA produced from the transgene would be destroyed in DRG neurons by the naturally present miR183, preventing protein production in these cells.

Researchers then compared the effects of administering AAV with a transgene containing or not containing miR183s sequence targets into the cerebrospinal fluid (the fluid that bathes the brain and spinal cord) of non-human primates.

Introducing miR183s sequence targets in the transgene were found to significantly reduce its mRNA levels and subsequent toxicity in DRG neurons, without affecting the transgenesmRNA levels elsewhere in the primates brain.

Steroids given to primates treated with unmodified AAVs, in contrast, failed to alleviate DRG damage, despite their known anti-inflammatory and immunosuppressive effects. This ineffectiveness was consistent with the proposal that immune system activity does not mediate this neuronal toxicity, the researchers wrote.

We were concerned about the DRG [toxicity] that was observed in most of our [non-human primate] studies, said James M. Wilson, MD, PhD, the studys senior author, and gene therapy program director and a professor of medicine and pediatrics at Penn Medicine.

This modified [viral] vectorshows great promise to reduce DRGtoxicityand should facilitate the development of safer AAV-based gene therapies for many CNS diseases, Wilson added.

Novartis gene therapy Zolgensma, when given directly into the bloodstream, is currently available for use in newborns and toddlers up to age 2 with any type of SMA in the U.S. and Japan, and to those with almost all types who weigh up to 21 kilograms (about 46 pounds) inEurope.

To meet aU.S. Food and Drug Administration(FDA) request for a pivotal confirmatory study of the gene therapys use with older SMA patients, who would be treated via intrathecal (IT) injection, Novartisplans to launch a new AVXS-101 IT trial.

This administration route is favored for those beyond toddler age, as it is thought to better target themotor neuronsdamaged by the disease.

According to the company, this IT trial cannot include U.S. sites until the hold on STRONG is lifted.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

Total Posts: 85

Ana holds a PhD in Immunology from the University of Lisbon and worked as a postdoctoral researcher at Instituto de Medicina Molecular (iMM) in Lisbon, Portugal. She graduated with a BSc in Genetics from the University of Newcastle and received a Masters in Biomolecular Archaeology from the University of Manchester, England. After leaving the lab to pursue a career in Science Communication, she served as the Director of Science Communication at iMM.

Read more:
Intrathecal Gene Therapy Use Might Be Safer With 'Silencing' Step - SMA News Today

For the first time, researchers at the Center for Cell-Based Therapy (CTC) in Ribeiro Preto, Brazil, have identified a non-hereditary mutation in blood cells from a patient with GATA2 deficiency.

GATA2 deficiency is a rare autosomal disease caused by inherited mutations in the gene that encodes GATA-binding protein 2 (GATA2), which regulates the expression of genes that play a role in developmental processes and cell renewal.

An article on the study is publishedin the journalBlood.

The non-hereditary mutation may have acted as a natural gene therapy which prevented the disease from damaging the process of blood cell renewal. This meant that the patient did not develop such typical clinical manifestations as bone marrow failure, hearing loss, and lymphedema.

The researchers say that the findings pave the way for the use of gene therapy and changes to the process of checking family medical history and medical records for families with the hereditary disorder.

Luiz Fernando Bazzo Catto, first author of the article, said: When a germline [inherited] mutation in GATA2 is detected, the patients family has to be investigated because there may be silent cases.

The discovery was made when two sons were receiving medical treatment at the blood centre of the hospital run by FMRP-USP, both of which, in post-mortem DNA sequencing, showed germline mutations and GATA2 deficiency diagnosis. The researchers used next generation sequencing to estimate the proportion of normal blood cells in the fathers bone marrow, preventing clinical manifestations of GATA2 deficiency, and of cells similar to his childrens showing that 93% of his leukocytes had the mutation that protects from the clinical manifestations of GATA2 deficiency.

Following the sequencing of the fathers T-lymphocytes, the researchers found that the mutation occurred early in their lives and in the development of hematopoietic stem cells, which have the potential to form blood.

They also measured the activity of the blood cells, to see if they could maintain the activity of inducing normal cell production for a long time, by measuring the telomeres of his peripheral blood leukocytes. Telomeres are repetitive sequences of non-coding DNA at the tip of chromosomes that protect them from damage. Each time cells divide, their telomeres become shorter. They eventually become so short that division is no longer possible, and the cells die or become senescent.

The telomeres analysed by the researchers were long, indicating that the cells can remain active for a long time.

The researchers hypothesised that the existence of the somatic mutation in the fathers blood cells, and its restoration of the blood cell renewal process, may have contributed to the non-manifestation of extra-haematological symptoms of GATA2 deficiency such as deafness, lymphedema, and thrombosis.

Professor Rodrigo Calado, a corresponding author of the article, said: A sort of natural gene therapy occurred in this patient. Its as if he embodied an experiment and a medium-term prospect of analogous gene therapy treatment in patients with GATA2 deficiency.

The findings help us understand better how stem cells can recover by repairing an initial genetic defect.

Recommended Related Articles

View post:
Non-hereditary mutation acts as natural gene therapy for GATA2 deficiency - Health Europa

Penn Medicine researchers have developed a new targeted approach to prevent a toxicity seen in the sensory neurons of dorsal root ganglia after gene therapy to treat neurological disorders. It's an important hurdle to clear, as the field works toward more safe and effective gene therapies for patients with disorders like spinal muscular atrophy.

"We believe that this new approach could improve safety in gene therapy universally," said first author Juliette Hordeaux, DVM, PhD, senior director of Translational Research in Penn's Gene Therapy Program.

The findings were reported online this week in theScience Translational Medicine.

The toxicity has not been reported in humans, but studies in nonhuman primates using adeno-associated viral (AAV) vectors to deliver corrected genes via the spinal cord fluid and intravenously have revealed problems of axonal degeneration in some tracts of the spinal cord and peripheral nerves. The cause was traced back to the dorsal root ganglion, or DRG, a cluster of neural cells on the outside of the spinal cord responsible for transmission of sensory messages.

This toxicity stems from the overexpression of an introduced gene, known as a transgene, in cells in the DRG, researchers from Penn's Gene Therapy Program found in the study. To correct that, they modified a transgene with a microRNA target designed to reduce the level of the transgene expression in the DRG. That alteration eliminated more than 80 percent of the transgene expression and reduced the toxicity in primates, the researchers report.

"We believe it is a safe, straightforward way to ameliorate the safety of AAV therapy for the central nervous system," said first author Juliette Hordeaux, DVM, PhD, senior director of Translational Research in Penn's Gene Therapy Program. "This approach could be used to design other gene therapy vectors to repress transgene expression in the cell types that are affected by the toxicity and not others, which is critical, because you need the expression everywhere else to effectively treat the disorder."

Gene transfer expert James M. Wilson, MD, PhD, director of the Gene Therapy Program, and professor of Medicine and Pediatrics in Penn's Perelman School of Medicine, served as the senior author of the paper.

After Penn researchers documented DRG toxicity in nonhuman primates, they began devising a way to overcome it. Though its asymptomatic in primates, the damage became clear under close study of histopathology in the CNS. Damage to the DRG in humans, researchers know, can lead to the breakdown of axons responsible for delivering impulses from nerves to the brain. Numbness and weakness in limbs, among other side effects, follow suit.

The observed toxicity in past animal studies was enough for the U.S. Food and Drug Administration to recently place a partial hold on human trials administering a gene therapy vector into the spinal cord to treat spinal muscular atrophy, the genetic disease that severely weakens muscles and causes problems with movement. In the new study, the researchers injected vectors with and without an microRNA target, first in mice and then primates. microRNA regulates gene expression and makes for an ideal target in the cells. microRNA-183 was chosen specifically because it is largely restricted to the neurons in the DRG.

Administering unmodified AAV vectors resulted in robust delivery of the new gene into target tissue and toxicity in DRG neurons. Vectors with the miRNA target, on the other hand, reduced transgene expression significantly, as well as the toxicity of DRG neurons, without affecting transduction elsewhere in the primate's brain, histological analyses of the specimens up to 90 days later showed. An immune response was first believed to be causing the toxicity; however, the researchers debunked that hypothesis through experiments that showed how immunosuppressants and steroids were unsuccessful at alleviating the toxicity.

According to the authors, toxicity of DRGs is likely to occur in any gene therapy that relies on high doses of a vector or direct delivery of a vector into the spinal cord fluid. This latest study paves a path forward to prevent that damage.

"We were concerned about the DRG pathology that was observed in most of our NHP studies," Wilson said. "This modified vector shows great promise to reduce DRG toxicity and should facilitate the development of safer AAV-based gene therapies for many CNS diseases."

Reference: Hordeaux J, Buza EL, Jeffrey B, et al. MicroRNA-mediated inhibition of transgene expression reduces dorsal root ganglion toxicity by AAV vectors in primates. Science Translational Medicine. 2020;12(569). doi:10.1126/scitranslmed.aba9188

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

See original here:
New Approach Reduces the Toxicity of Brain-Targeted Gene Therapy - Technology Networks

Belgium-headquartered UCB has strengthened its gene therapy capabilities with a pair of deals a collaboration agreement with Lacerta Therapeutics and the acquisition of Handl Therapeutics.

Handl Therapeutics based in Leuven, Belgium specialises in adeno-associated virus (AAV) capsid technology and has a focus on developing disease modifying gene therapies to treat neurodegenerative diseases.

In addition to its own capabilities, Handl has built an international network to access expertise from a number of institutions. This includes platforms licensed from KU Leuven in Belgium, the Centre for Applied Medical Research in Spain, the University of Chile and Kings College London in the UK.

UCBs global footprint and scientific expertise in neurodegenerative diseases, coupled with our shared cultures of scientific advancement and commitment to patients, creates an exceptional environment in which we can accelerate the development of gene therapies and change patients lives, said Florent Gros, founder and chief executive officer of Handl Therapeutics.

UCB did not disclose the financial terms of the acquisition, although it did add in a statement that the Handl team will continue to be based in Handl and will work closely with UCBs international research team.

The Lacerta deal is focused on developing AAV-based therapies for patients with a central nervous system disease with a high unmet need. Like the Handl acquisition, UCB did not offer the financial details of the Lacerta research collaboration and licensing agreement.

Lacerta is set to lead research and preclinical activities as well as the early manufacturing process development, with UCB planning to lead IND-enabling studies, manufacturing and clinical development.

UCBs ambition for patients relies on our ability to innovate and deliver highly differentiated medicines, said Dhavalkumar Patel, chief scientific officer of UCB.

The acquisition of Handl Therapeutics and the new partnership with Lacerta Therapeutics offers us the potential to drive a fundamental change in how diseases are treated, by moving us from treating symptoms to disease modification and eventually towards a cure. he added.

The Handl and Lacerta deals build on UCBs previous acquisition of Element Genomics in 2018.

UCB paid $30m to access Elements platform of technologies aimed at improving the understanding of genome structure and function including CRISPR editing technologies used for genomic and epigenomic regulatory region analysis and modulation.

Go here to see the original:
UCB boosts gene therapy offering with a pair of new deals - PMLiVE

Researchers from Penn Medicine have developed a new targeted approach that modifies viral vectors and inhibits toxicities in the sensory neurons of dorsal root ganglia (DRG) that commonly occur following the use of gene therapy for neurological diseases.

This strategy will likely have several important research and clinical implications, as investigators in the field have worked tirelessly for years to develop safer and more effective gene therapies for neurological disorders. We believe that this new approach could improve safety in gene therapy universally, said lead author Juliette Hordeaux, DVM, Ph.D., senior director of Translational Research in Penns Gene Therapy Program, in a statement.

Many gene therapies use viral vectors, but these vectors can have adverse neurological effects. While these toxicities have not yet been observed in humans, nonhuman primate studies using adeno-associated viral (AAV) vectors to deliver corrected genes via the spinal cord fluid have shown issues of axonal degeneration in spinal cord and peripheral nerve tracts. In these studies, the cause of the issues led back to the DRG, comprising a cluster of neural cells found on the outside of the spinal cord that are responsible for delivering sensory messages.

In a recent paper published in Science Translational Medicine, Dr. Hordeaux and colleagues found a way of modifying these vectors so they ultimately avoid these dangerous side effects. They first found that the toxicities appear to come from overexpression of a transgene in cells in the DRG.

The researchers altered a transgene with a microRNA target that was designed to reduce transgene expression levels in the DRG. Ultimately, this modification eliminated over 80% of the transgene expression and resulted in drastic toxicity reduction in the studied primates

We believe it is a safe, straightforward way to ameliorate the safety of AAV therapy for the central nervous system, said Hordeaux about the studied modification. This approach could be used to design other gene therapy vectors to repress transgene expression in the cell types that are affected by the toxicity and not others, which is critical, because you need the expression everywhere else to effectively treat the disorder.

Senior author of the paper was gene transfer expert James M. Wilson, MD, Ph.D., professor of Medicine and Pediatrics in Penns Perelman School of Medicine. Dr. Wilson, who left Solid Biosciences two years ago. Dr. Wilson has been discussing the potential adverse neurological effects of AAV vectors for several years.

Drs. Hordeaux and Wilson injected vectors with and without a microRNA target miRNA183 in mice and primates in the new study. The administration of unaltered AAV vectors led to robust delivery of the gene into target tissue as well as toxicities in DRG neurons. These effects occurred without impacting transduction in elsewhere in the brain, according to histological analyses conducted up to 90 days later.

The authors of the study suggest the toxicity of DRGs likely occur in a gene therapy relying on high vector doses or direct vector delivery into the fluid of the spinal cord. We were concerned about the DRG pathology that was observed in most of our nonhuman primate studies, noted Wilson. This modified vector shows great promise to reduce DRG toxicity and should facilitate the development of safer AAV-based gene therapies for many central nervous system diseases.

Go here to see the original:
New Targeted Approach Could Prevent Toxicities Associated with Neurological Gene Therapies - BioSpace