Category Archives: Gene therapy

The human brain develops through a delicate process where nerve cells grow, move to the right spots, and arrange themselves into functional layers. Abnormalities in this intricate coordination cause malformations in the brain's cortex, leading to focal cortical dysplasia (FCD), the most common cause of epilepsy in children. Patients with FCD are often resistant to anti-epileptic therapy. Surgery to remove the malformed parts of the brain is the standard treatment, which risks altering normal brain function.

In a recent study, researchers at University College London showed that a gene therapy targeted at cortical neurons significantly reduced the frequency of FCD-induced seizures in adult mice (1). It's proof of concept that gene therapy can work after seizures have started, said Angeligue Bordey, a neuroscientist at the Yale School of Medicine who was not involved in the study but who also tested an early treatment to correct seizures before they occurred (2).

Gabriele Lignani led the team that developed a gene therapy to directly address seizures in mice.

credit: Gabriele Lignani

The researchers focused on developing a gene therapy that could directly address seizures, a symptom common to all patients with epilepsy, regardless of cause. By targeting seizure reduction, they aimed to develop a universally applicable treatment. If we decrease the seizures in [FCD] patients, we can have a treatment for all [epilepsy] patients, said Gabriele Lignani, a translational neuroscientist at University College London and study coauthor.

The gene therapy did the job of an antiepileptic drug but was targeted to a specific brain region to mitigate seizures and minimize the side effects typically associated with systemic medications. It's a bit of a different way of doing gene therapy, compared to just correcting a mutation that is really specific for a patient and sometimes more specific to the mouse model than to the patient, Lignani said.

Lignanis research team used an existing mouse model of FCD that involves introducing genetic material into the developing brain of mouse embryos using in utero electroporation. They used a plasmid carrying both a fluorescent marker for easy visualization and a constitutively active Ras homolog enriched in brain (RHEB), an activator of the mechanistic target of rapamycin (mTOR) pathway. Overactivation of mTOR resulted in the characteristic features of FCD, including dysmorphic, enlarged, and misplaced neurons.

To monitor brain activity, the researchers implanted the mice with subcutaneous wireless electrocorticography transmitters positioned over areas showing successful electroporation. This setup allowed for continuous baseline monitoring of brain activity. After 10-15 days of recording, they found that about 65 percent of the electroporated animals exhibited generalized seizures and showed learning disability and impaired social cognition often seen in patients with FCD.

After establishing baseline seizure activity in the mice, the next step was to evaluate the effect of a gene therapy based on overexpression of the Kv1.1 potassium channel, a type of voltage-gated potassium channel that regulates neuronal excitability. Overexpressing Kv1.1 can enhance the outward flow of K+ ions, making neurons less likely to fire excessively, which is a common problem in epilepsy. This channel seems quite good at decreasing excitability and decreasing seizures, Lignani said.

It's a bit of a different way of doing gene therapy compared to just correcting a mutation that is really specific for a patient and sometimes more specific to the mouse model than to the patient. - Gabriele Lignani, University College London

The researchers designed the potassium channel transgene to be most active in the brains main excitatory neurons and packaged it in an adeno-associated viral vector (AAV9). Lignanis team used a cannula to deliver the treatment and monitored brain activity to assess the impact of gene therapy on seizures.

Mice treated with the gene therapy showed a 64 percent reduction in seizures compared to their baselines, with 60 percent of treated animals becoming seizure-free by the end of the observation period. It's a pretty significant reduction, said Bordey. These experiments are very hard to do, so that's an enormous amount of work done.

Lignani believes that this gene therapy could be a viable alternative to surgery for patients with epilepsy. If [gene therapy] works and you don't have seizures, that's it. If it doesn't work, we still have the surgery [to fall back on], he said.

This gene therapy also looks promising for patients with FCD in brain regions where surgery is not an option. Its less invasive, meaning that you need to make a small hole to inject the virus, instead of taking out a big part of the brain, said Lignani.

However, Bordey said that AAV gene therapy comes with its own risks. Once you put it in, it's there for at least five or ten years, she said. If you have a side effect, you're stuck with it.

Lignanis team is gearing up to start a clinical trial in adult patients before expanding to include pediatric cases. This decision is grounded in a comprehensive body of translational preclinical work (3,4). That gives us assurance that we have a good effect, he said. We are quite confident that it works.

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An alternative to brain surgery for patients with epilepsy - Drug Discovery News

Gene therapy research is booming. Since the U.S. Food and Drug Administration (FDA) issued its first approval for a gene therapyin 2017, oncology researchers have been breaking barriers in gene therapy trials, followed by an explosion in mRNA research during the COVID pandemic. Today, this trailblazing science is providing new ways to approach rare diseases and new hope when other investigational interventions have failed. In fact, themajorityof approved gene therapies are for rare diseases 14 are currently in Phase III trials for 10 rare diseases and 45 gene therapies are in early stages of development to treat 30 rare diseases. We see great potential for gene therapies, said Leslie Johnston, senior vice president of biotech delivery for Parexel. As more products are approved, it will gain traction and more companies will look to expand their therapies into other therapeutic indications. This progress presents tremendous potential to change more patients lives across many different diseases. This could be gene therapys moment. But to fully seize it, the industry must clear some complex hurdles. Gene therapies pose several unique challenges for clinical research, including ethical and safety considerations, regulatory hurdles, precarious logistics, and potentially staggering costs. These challenges may already be having ramifications: New U.S. patients treated with gene therapies approved or in development areexpected to fallby one-third from 2025 to 2034. The key to clearing these hurdles? Cooperation between sponsors, sites, regulators, patients, and other stakeholders is essential to expediting the advancement of life-saving gene therapies. Regulators should address risks without limiting innovation Gene therapy trials are strictly regulated and rightly so, due to the novel nature of the intervention and the potential long-term consequences. Gene therapy interventions also carry inherent safety risks, including the potential for unintended genetic changes or adverse immune reactions. Ensuring patient safety requires rigorous monitoring and adherence to strict protocols. However, obtaining regulatory approval under these conditions is time consuming and resource intensive. To avoid hampering scientific progress, regulators should aim to ensure that requirements are appropriately rigorous without being unmanageably onerous. Thankfully, the FDA is paying close attention to gene therapy and has demonstrated a desire to work with drug developers toward the success and approval of these treatments. Dr. Peter Marks, Director of the Center for Biologics Evaluation and Research (CBER) at the FDA, has expressed his hope for an exponential, if not logarithmic, increase in gene therapy approvals. There is a lot of excitement that this could potentially make a big difference for the treatment of human disease, said Dr. Marks in hisremarksto the National Press Forum last November. The FDA is going beyond mere rhapsodizing and taking action to accelerate gene therapy. Last year, the agencylaunched a pilot programcalled Support for Clinical Trials Advancing Rare Disease Therapeutics, or START. This program is designed to accelerate the development and approval process for treatments targeting rare diseases by providing regulatory guidance, assistance, and incentives to sponsors conducting clinical trials in this field. The program represents an important step forward in fostering innovation and collaboration between regulatory bodies and sponsors. In addition, the FDA is working toharmonize global requirementsfor the review of gene therapies. Encouraging and facilitating international cooperation and harmonization of regulatory standards including mutual recognition agreements and shared regulatory pathways for multinational clinical trials can help streamline gene therapy development globally and help bring innovations to patients faster. Even with this progress, regulators should continue to help accelerate gene therapy research by streamlining regulatory pathways specifically tailored to gene therapies. This means providing clear guidance on requirements for preclinical and clinical development, fostering collaboration between stakeholders to share knowledge and best practices, and offering expedited review processes for gene therapy products aimed at treating serious or life-threatening diseases. With a staggering2,500 cell and gene therapyinvestigational new drug applications (INDs) on file, the FDA approved justfivecell and gene therapies in 2023. Dr. Marks hassuggestedthat accelerated approval, which has successfully advanced cancer and HIV/AIDS treatments, may be the most appropriate path for this new category of treatments. But, regulators also need to commit to proactively partner with developers to understand the patient population and the risks and benefits of each new therapy. Likewise, researchers, industry stakeholders, and patient advocacy groups should engage with regulators to help them understand the unique challenges and opportunities in the field of gene therapy. This can help regulators adapt regulatory frameworks to ensure patient safety while expediting the development and approval of promising treatments. Sites and sponsors must be prepared Of course, sites and sponsors also have a crucial part to play in advancing this promising field of medicine. Clinical trial sites should enhance their capacity to conduct gene therapy trials safely and effectively and sponsors should do their part to assist sites in these efforts. By working closely with clinicians and regulators, sponsors can ensure that the trial development process aligns with clinical needs and regulatory standards. Sponsors should have a thorough understanding of FDA requirements pertaining to design, preclinical testing, and long-term follow-up. Better alignment from the outset will lead to more efficient trial designs, faster regulatory approvals, and ultimately quicker patient access to therapies. For example, sponsors working with mRNA and other genetically engineered therapies in North America not only have to go through institutional review board (IRB) review, they also have to navigate additional requirements from the U.S. National Institutes of Health (NIH) Office of Science PolicyGuidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules(NIH Guidelines). These requirements usually involve an additional biosafety risk assessment review from an institutional biosafety committee (IBC) in addition to IRB review. NIH Guidelines apply for any research involving recombinant or synthetic nucleic acids (e.g. genetically engineered materials) that receives NIH support or takes place at sites that have received NIH support for such research. Even when there is zero NIH support, IBC review is considered a best practice. IBC review and inspection helps sites ensure they are fully prepared by identifying areas for improved biosafety protections and calling out gaps in current standard operating procedures (SOPs). Proactive coordination and integration of these separate review processes can speed trial timelines and help sponsors consistently address any potential concerns or issues. Sites can also be better prepared by pre-registering an IBC. The NIH takes six to eight weeks or more to approve a new registration, in addition to IBC review time so by registering an IBC before they even have a trial, sites can save a month or more in startup time over a site that waited to register. Clinical trial sites looking to host gene therapy studies must be prepared in other ways, as well, both in terms of knowledge and infrastructure. Gene therapy studies require specialized infrastructure for manufacturing, storing, and administering genetic material to adhere to strict biosafety guidelines. Something as simple as having an upholstered chair in the infusion room which would pose an unacceptable contamination risk if genetic materials were to spill would require the site to rethink their current processes. Rigorous training is also key due to the added risk of spreading genetic material to caregivers and others in close contact with patients. Research staff must be specially trained to handle, deliver, and dispose of this material safely. Of course, these measures can seem intimidating for sites that are already cost-constrained. Large academic medical centers with more resources and experience are more likely to be well-positioned for these studies. For instance, they may already have conducted bench, animal, and/or agricultural research with genetic engineering or have the funding to make any needed adjustments such as purchasing special equipment. But to maximize the potential number of sites where this research can be conducted and therefore reach more potential participants sponsors might consider providing help in the form of financial assistance, training curricula, SOP guidance, and more to smaller sites seeking to conduct gene therapy research. Logistical complexities depending on the investigational medicine and therapeutic area are among the most complicated challenges in gene therapy trials, added Johnston. From collecting the specimen from the patient, modifying it, storing it, transporting it, and then returning it back to the patient all comes with tremendously unique logistical challenges and requires equally unique equipment, technology, and expertise. And it can be cost-prohibitive. Patients must be fully on board Of course, the most essential stakeholder in any clinical trial is the patient. In gene therapy research, which can be particularly demanding, patients must have a complete understanding of and commitment to their involvement. Understanding the potential risks and benefits can help patients make informed decisions and navigate the study process. First, it's crucial for patients to adhere strictly to the protocol provided by the clinical trial team, including following medication schedules, maintaining specific hygiene practices, and attending all study visits. They should strive to maintain optimal health to enhance the body's response to gene therapy. And to avoid delays, patients should maintain open and honest communication with the clinical trial team, reporting any changes in symptoms, side effects, or general health as soon as they occur. Trial participants also need to be in it for the long haul. Because gene therapy interventions aim to produce lasting effects, even cures, they typically require long-term patient follow-up to assess efficacy and safety. But they may also need to have incredible patience. Johnston explained, There are many complexities that can impact study progress. For example, unpredictable logistical challenges like a weather event or vehicle accident could delay a temperature-sensitive delivery to a site, or data review outcomes could require an indeterminate pause period. Patience and agility are must-haves, but it is difficult for patients potentially depending on this new therapy to save or change their lives. Lastly, the industry cannot forget the patient. Involving patients and patient advocacy groups in the regulatory process can help ensure that the development of gene therapies is aligned with patient needs and priorities, as well as shed light on risk-benefit perspectives from a patients viewpoint. The more these perspectives are considered from the beginning, the greater the chance of a trials success. Rita Naman, co-founder of the Mighty Milo Foundation, emphasizes the need for a more collaborative and patient-centered approach to gene therapy development. "For ultra-rare diseases likeSPAX5, gene therapy offers a glimmer of hope where traditional treatments do not. But logistical hurdles make these therapies expensive and inaccessible, explained Naman. Closer collaboration with patients, industry, and regulators could streamline these processes, drive costs down, and speed trials. Patients like my son, and their caregivers, plus advocacy groups should be invited into the earliest discussions to prevent false starts or missed milestones in gene therapy development especially as the patients priorities dont always line up with the sponsors. In the fight for gene therapy breakthroughs, cooperation is key. The road to operationalizing gene therapy clinical trials is laced with land mines and potholes. To capture the full potential of novel gene therapy research, a new level of collaboration between sponsors, CROs, sites, oversight committees, regulatory bodies, and patients is paramount. Patients want access to novel gene treatments, and they want it fast. Sponsors want to deliver but fight logistical and financial obstacles. Regulators want to ensure safety first, especially considering such new, promising science, concluded Johnston. These three goals may seem conflicting at times, so we need to strike a balance of safety and speed, so patients dont miss their only potential treatment opportunity. A seasoned industry veteran with more than 25 years of experience, James Riddle is senior vice president of global review operations at Advarra. Riddles expertise includes large program management and growth, operational processes, development and implementation of technology solutions, and management of large Human Research Protection Programs (HRPP), Biosafety programs (IBC) and Institutional Animal Care and Use programs (IACUC). Riddle has directed numerous clients in achieving Part 11 compliance and meeting computer system validation requirements.

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Gene Therapy is Having its Moment: Can the Clinical Research Ecosystem Seize It? - Contract Pharma

CGT Catapult and CATTI have developed aligned training standards for the manufacture of advanced therapies.

On May 30, 2024, Cell and Gene Therapy Catapult (CGT Catapult) and the Canadian Advanced Therapies Training Institute (CATTI) announced that they developed a strategy that aligns training standards and assessment for the advanced therapies manufacturing industry. The strategy establishes an important first move toward building shared standards to help the advanced therapies manufacturing industry access a skilled workforce, according to a press release.

Advanced therapies are manufactured by highly trained personnel who are good manufacturing practice (GMP)-certified and who know how to operate in aseptic conditions. The current training and assessment for these personnel varies around the world, which makes it difficult for the workforce to relocate and for the industry to access global talent.

This partnership marks a crucial step towards ensuring that our workforce is equipped with the highest level of expertise to meet industry demands. By setting these international standards, we aim to enhance the quality and safety of advanced therapies, ultimately benefiting patients worldwide, said Vanessa Laflamme, CEO of CATTI, in the press release.

CATTI and the CGT Catapult first formed a collaboration in 2023 under which they aim to increase the levels of standardization in the training and assessment standards used in Canada and the United Kingdom. Since then, the organizations have aligned training materials and programs and have outlined a joint strategy that specifies which specific skills and competencies should be assessed. The goal is to establish a rigorous template that can then be applied across all manufacturing training materials and across various skill levels.

By sharing expertise and working with CATTI, a leading provider of training for the advanced therapies industry, we have a valuable opportunity to enhance and standardize the training available to organizations and individuals. This builds on the efforts of the CGT Catapult to date and the investment we have made, alongside government, in developing a successful training program for the UK workforce. Together, we aim to ensure that our growing global sector is supported by a highly skilled workforce equipped with the latest knowledge and skills, said Matthew Durdy, chief executive, CGT Catapult in the release.

CATTI also partnered with bioMrieux Canada in December 2023 to combine their capabilities to enhance workforce training in advanced therapies and the production of quality control solutions for the bio/pharmaceutical industry (1). Under this agreement, bioMrieux is responsible for deploying more than half a million dollars worth of analytical equipment and services in the CATTI training laboratory located at the University of Guelph in Ontario, Canada. The training under this collaboration will equip highly qualified, GMP-certified personnel who are qualified to work under aseptic conditions with the skills and knowledge to manufacture anticancer immunotherapies, cell and gene therapies, vaccines, and other biotherapeutic applications.

1. Canadian Advanced Therapies Training Institute. CATTI and bioMrieux Canada are Joining Forces to Support the Development of a Qualified Workforce in Advanced Therapies. Press Release, Dec. 7, 2023.

Source: CGT Catapult

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CGT Catapult Joins Forces with CATTI to Create Manufacturing Training Standards for Advanced Therapies - BioPharm International

New container developed for the needs of cell and gene therapy (CGT) primary packaging to replace cryopreservation bags with a fracture resistant, rigid construction built for both manual use and closed-system automation.

BOTHELL, Wash., May 29, 2024 /PRNewswire/ -- BioLife Solutions, Inc.(NASDAQ: BLFS), a leading supplier of bioproduction tools and services for the cell and gene therapy (CGT) and broader biopharma markets, today announced the introduction of the CryoCase, an addition to its CellSeal product line.

"Particulates in drug product is a growing problem that we believe can be reduced with better primary containers."

Expected to be released toCGT developers in August, the CryoCase is available for demonstration at this week's ISCT event in Vancouver, Canada. Early product evaluators stated that the CryoCase's volume versatility, rigid and protective structure, and fill and retrieval port designs, allows for easy integration with their current systems generating improved throughput and streamlined procedures.

The CryoCase is the first ever cryo-compatible rigid container designed for closed-system fill and retrieval for larger volumes of fluid (<75mL). The container is transparent, enabling improved end user compliance with USP 790, USP 1790, and other international visible inspection methods, and manufactured under strict environmental and processing controls designed to limit common sources of particulates in single-use disposable manufacturing. Early user testing has shown comparable cell viability and recovery for multiple cell types compared to storage in existing bags and drop testing in a frozen state demonstrates high resistance to leaks or fractures. Initial testing indicates that the CryoCase may materially reduce or eliminate particulates inherent in cryopreservation bags.

"Particulates in reagent manufacturing and final drug product is a growing problem that we believe can be reduced with better primary containers and true, closed-system approaches to CGT manufacturing," stated Todd Berard, Chief Marketing Officer. "The CryoCase is compatible with various downstream processing systems including our Signata CT-5, and we believe it can reduce overall risks and costs involved in creating and distributing these lifesaving therapies."

CryoCase samples are now available for testing. Contact your BioLife Solutions representative for more information.

About BioLife SolutionsBioLife Solutions is a leading supplier of class-defining bioproduction tools and services for the cell and gene therapy (CGT) and broader biopharma markets. Our expertise facilitates the commercialization of new therapies by supplying solutions that maintain the health and function of biologic materials during collection, development, storage, and distribution. For more information, please visit http://www.biolifesolutions.com or follow BioLife on LinkedIn and X.

Media & Investor Relations

At the CompanyTroy Wichterman Chief Financial Officer (425) 402-1400 [emailprotected]

Investors LHA Investor Relations Jody Cain (310) 691-7100 [emailprotected]

SOURCE BioLife Solutions, Inc.

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BioLife Solutions Introduces the CellSeal CryoCase at International Society for Cell & Gene Therapies (ISCT ... - PR Newswire

~ Designation based on 24-month interim Phase I/II clinical data for AMT-130 announced in December 2023 ~

~ AMT-130 is the first therapeutic candidate to receive RMAT Designation for Huntingtons disease ~

~ Receiving RMAT designation enables increased collaboration with the FDA on regulatory approval planning, in addition to the opportunity for expedited product development ~

LEXINGTON, Mass. and AMSTERDAM, June 03, 2024 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced that the U.S. Food and Drug Administration (FDA) has granted Regenerative Medicine Advanced Therapy (RMAT) designation for its investigational gene therapy AMT-130 for the treatment of Huntingtons disease.

The FDA granted RMAT designation based on the potential of AMT-130 to address the major unmet medical need among patients with Huntingtons disease. The designation follows the FDAs review of interim Phase I/II clinical data for AMT-130 announced in December 2023 and is based on an analysis comparing these 24-month clinical data to a non-concurrent criteria-matched natural history cohort.

Were thrilled to receive the first ever RMAT designation for an investigational therapy for Huntingtons disease, stated Matt Kapusta, chief executive officer of uniQure. This achievement is a significant milestone for the program and supports the potential for AMT-130 to address the high unmet medical need of those suffering from this devastating disease.

The RMAT designation, which was based on the comparison of the two-year AMT-130 data to a natural history cohort, marks a promising start to our FDA interactions, stated Walid Abi-Saab, chief medical officer of uniQure. Importantly, RMAT designation allows for increased collaboration with the FDA to accelerate development, potentially facilitating earlier access for patients with life-threatening medical conditions. Im incredibly proud of the team at uniQure for this accomplishment, and we look forward to presenting updated interim data from our ongoing Phase I/II studies in the middle of the year.

RMAT designation was created as part of the 21st Century Cures Act to expedite the development and review processes of regenerative medicine therapies. A regenerative medicine therapy can be eligible for RMAT designation if it is intended to treat, modify, reverse or cure a serious condition, and if preliminary clinical evidence indicates that the drug has the potential to address unmet medical needs for such a condition. Receiving RMAT designation offers sponsor companies all the benefits of the fast track and breakthrough therapy designation programs, allowing for early, close and frequent interactions with the FDA. This includes opportunities for early agency interactions to discuss the use of surrogate or intermediate endpoints, potential approval pathways including ways to support accelerated approval, and other opportunities to expedite development.

uniQure expects to provide updated interim data from the ongoing Phase I/II U.S. and European studies of AMT-130 in the middle of 2024. The interim update will include up to three years of follow-up on 29 treated patients, 21 of which will have been followed for at least two years.

About the Phase I/II Clinical Program of AMT-130

TheU.S.Phase I/II clinical trial of AMT-130 for the treatment of Huntingtons disease is exploring the safety, tolerability, and efficacy signals in 26 patients with early manifest Huntingtons disease split into a 10-patient low-dose cohort followed by a 16-patient high-dose cohort. Patients are randomized to treatment with AMT-130 or an imitation (sham) surgery. The multi-center trial consists of a blinded 12-month core study period followed by unblinded long-term follow-up for a period of up five years. A total of 16 patients in the clinical trial were randomized to treatment and received a single administration of AMT-130 through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen). An additional four control patients in the high-dose cohort crossed over to treatment following the core study period. Additional details are available onwww.clinicaltrials.gov(NCT04120493).

The European, open-label Phase Ib/II study of AMT-130 enrolled 13 patients with early manifest Huntingtons disease across two dose cohorts; a low-dose cohort of six patients and a high-dose cohort of seven patients. Together with theU.S.study, the European study is intended to establish safety, proof of concept, and the optimal dose of AMT-130 to take forward into Phase III development or into a confirmatory study should an accelerated registration pathway be feasible.

Patient dosing is ongoing in a third cohort of up to 12 patients to further evaluate both doses of AMT-130 in combination with perioperative immunosuppression. Enrollment in this third cohort is expected to be completed in the second half of 2024. AMT-130 is uniQures first clinical program focusing on the central nervous system incorporating its proprietary miQUREplatform.

About Huntingtons Disease

Huntingtons disease is a rare, inherited neurodegenerative disorder that leads to motor symptoms including chorea, behavioral abnormalities and cognitive decline resulting in progressive physical and mental deterioration. The disease is an autosomal dominant condition with a disease-causing CAG repeat expansion in the first exon of the huntingtin gene that leads to the production and aggregation of abnormal protein in the brain. Despite the clear etiology of Huntingtons disease, there are currently no approved therapies to delay the onset or to slow the diseases progression.

About uniQure

uniQures mission is to reimagine the future of medicine by delivering innovative cures that transform lives. The recent approvals of our gene therapy for hemophilia B a historic achievement based on more than a decade of research and clinical development represent a major milestone in the field of genomic medicine and ushers in a new treatment approach for patients living with hemophilia. We are now leveraging our modular and validated technology and manufacturing platform to advance a pipeline of proprietary gene therapies for the treatment of patients with Huntington's disease, refractory mesial temporal lobe epilepsy, amyotrophic lateral sclerosis (ALS), Fabry disease, and other severe diseases.www.uniQure.com

uniQure Forward-Looking Statements

This press release contains forward-looking statements. All statements other than statements of historical fact are forward-looking statements, which are often indicated by terms such as "anticipate," "believe," "could," establish, "estimate," "expect," "goal," "intend," "look forward to", "may," "plan," "potential," "predict," "project," seek, "should," "will," "would" and similar expressions. Forward-looking statements are based on management's beliefs and assumptions and on information available to management only as of the date of this press release. Examples of these forward-looking statements include, but are not limited to, statements concerning the potential of AMT-130 to address the unmet medical needs of Huntingtons disease patients; the potential that RMAT designation will expedite the ongoing development of AMT-130 and facilitate earlier access to Huntingtons disease patients; the Companys plans to present updated interim data from the ongoing Phase I/II U.S. and European studies of AMT-130 in mid-2024; and the Companys plans regarding the third cohort in its AMT-130 clinical trial and the timing of enrollment for such cohort. The Companys actual results could differ materially from those anticipated in these forward-looking statements for many reasons. These risks and uncertainties include, among others: risks associated with the Companys clinical results and the development and timing of its programs; the Companys interactions with regulatory authorities, which may affect the initiation, timing and progress of clinical trials and pathways to regulatory approval; whether RMAT designation or any accelerated pathway will lead to regulatory approval; the Companys ability to conduct and fund a Phase III or confirmatory study for AMT-130; the Companys ability to continue to build and maintain the company infrastructure and personnel needed to achieve its goals; the Companys effectiveness in managing current and future clinical trials and regulatory processes; the continued development and acceptance of gene therapies; the Companys ability to demonstrate the therapeutic benefits of its gene therapy candidates in clinical trials; the Companys ability to obtain, maintain and protect its intellectual property; and the Companys ability to fund its operations and to raise additional capital as needed. These risks and uncertainties are more fully described under the heading "Risk Factors" in the Companys periodic filings with the U.S. Securities & Exchange Commission (SEC), including its Annual Report on Form 10-K filed February 28, 2024 and in other filings that the Company makes with the SEC from time to time. Given these risks, uncertainties and other factors, you should not place undue reliance on these forward-looking statements, and the Company assumes no obligation to update these forward-looking statements, even if new information becomes available in the future.

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uniQure Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for Investigational Gene ... - GlobeNewswire

A toddler who was born completely deaf due to a rare genetic condition can now hear unaided thanks to a pioneering gene therapy.

Opal Sandy, who is now an 18-month-old girl from the U.K., is the youngest child in the world to receive this type of gene therapy, which uses a harmless, modified virus to correct genetic mutations in the body's cells. In this case, the therapy replaced a mutant gene associated with deafness with a working copy of that gene, according to a statement released May 9 by Cambridge University Hospitals.

Very similar gene therapies are being tested in other trials and have shown early success in treating slightly older children with the same type of hearing loss as Opal.

Known as auditory neuropathy, this type of hearing loss arises when the ears can detect sound but can't relay that information to the brain. The condition is caused by mutations in a gene called OTOF that normally makes otoferlin, a protein needed for the inner ear to talk to neurons that are linked to the brain. The condition accounts for between 1% and 8% of cases of congenital hearing loss that occurs in the absence of other symptoms.

Related: CRISPR can treat common form of inherited blindness, early data hint

Opal was diagnosed at 3 weeks old. When she was 11 months old she became the first patient treated in a global trial of the new gene therapy. She was given the new treatment via an injection into her right ear. The virus injected during the procedure known as an adeno-associated virus delivers a working copy of OTOF to cells in the ear to replace the mutated version. Afterwards, the virus is naturally eliminated from the body.

Doctors also installed a cochlear implant in Opal's left ear; these devices help users hear some sound by relaying signals to the brain that their ear cells can't.

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Within four weeks of the gene therapy, Opal could respond to sounds even when her cochlear implant was switched off, her doctors reported. Twenty-four weeks out from treatment, her treated ear could pick up soft sounds, such as whispering, at "close to normal" hearing levels. Now, at 18 months old, Sandy can respond to her parents' voices without her implant activated and say words such as "dada" and "bye-bye."

"When Opal could first hear us clapping unaided it was mind-blowing we were so happy when the clinical team confirmed at 24 weeks that her hearing was also picking up softer sounds and speech," Opal's mother Jo said in the statement. Her father, James, noted that Opal can't wear her implant in certain contexts, such as in the bath, so the therapy is already making a difference in their day-to-day lives.

The ongoing trial that Opal is part of is enrolling patients in the U.S., the U.K. and Spain. In this stage of the research, patients receive a low dose of the therapy in one ear. Future trials will test the therapy at higher doses in one ear and then in both ears. Patients will be followed up for five years to assess long-term outcomes.

"Gene therapy has been the future of otology and audiology for many years and I'm so excited that it is now finally here," Dr. Manohar Bance, chief investigator of the trial and a professor of otology and skull base surgery at the University of Cambridge in the U.K., said in the statement.

"This is hopefully the start of a new era for gene therapies for the inner ear and many types of hearing loss," he said.

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Deaf baby can hear after 'mind-blowing' gene therapy treatment - Livescience.com

Disc-related back pain may one day meet its therapeutic match: gene therapy delivered by naturally derived nanocarriers that, a new study shows, repairs damaged discs in the spine and lowers pain symptoms in mice.

Scientists engineered nanocarriers using mouse connective-tissue cells called fibroblasts as a model of skin cells and loaded them with genetic material for a protein key to tissue development. The team injected a solution containing the carriers into damaged discs in mice at the same time the back injury occurred.

Assessing outcomes over 12 weeks, researchers found through imaging, tissue analysis, and mechanical and behavioral tests that the gene therapy restored structural integrity and function to degenerated discs and reduced signs of back pain in the animals.

We have this unique strategy thats able to both regenerate tissue and inhibit some symptoms of pain, said co-senior author Devina Purmessur Walter, associate professor of biomedical engineering at The Ohio State University.

Though there is more to learn, the findings suggest gene therapy could offer an effective and long-lasting alternative to opioids for the management of debilitating back pain.

This can be used at the same time as surgery to actually boost healing of the disc itself, said co-senior author Natalia Higuita-Castro, associate professor of biomedical engineering and neurological surgery at Ohio State. Your own cells are actually doing the work and going back to a healthy state.

The study was published online recently in the journal Biomaterials.

An estimated 40% of low-back pain cases are attributed to degeneration of the cushiony intervertebral discs that absorb shocks and provide flexibility to the spine, previous research suggests. And while trimming away bulging tissue from a herniated disc during surgery typically reduces pain, it does not repair the disc itself which continues to degenerate with the passage of time.

Once you take a piece away, the tissue decompresses like a flat tire, Purmessur Walter said. The disease process continues, and impacts the other discs on either side because youre losing that pressure that is critical for spinal function. Clinicians dont have a good way of addressing that.

This new study builds upon previous work in Higuita-Castros lab, which reported a year ago that nanocarriers called extracellular vesicles loaded with anti-inflammatory cargo curbed tissue injury in damaged mouse lungs. The engineered carriers are replicas of the natural extracellular vesicles that circulate in humans bloodstream and biological fluids, carrying messages between cells.

To create the vesicles, scientists apply an electrical charge to a donor cell to transiently open holes in its membrane, and deliver externally obtained DNA inside that converts to a specific protein, as well as molecules that prompt the manufacture of even more of a functional protein.

In this study, the cargo consisted of material to produce a pioneer transcription factor protein called FOXF1, which is important in the development and growth of tissues.

Our concept is recapitulating development: FOXF1 is expressed during development and in healthy tissue, but it decreases with age, Purmessur Walter said. Were basically trying to trick the cells and give them a boost back to their developmental state when theyre growing and at their healthiest.

In experiments, mice with injured discs treated with FOXF1 nanocarriers were compared to injured mice given saline or mock nanocarriers and uninjured mice.

Compared to controls, the discs in mice receiving gene therapy showed a host of improvements: The tissue plumped back up and became more stable through production of a protein that holds water and other matrix proteins, all helping promote range of motion, load bearing and flexibility in the spine. Behavioral tests showed the therapy decreased symptoms of pain in mice, though these responses differed by sex males and females showed varying levels of susceptibility to pain based on the types of movement being assessed.

The findings speak to the value of using universal adult donor cells to create these extracellular vesicle therapies, the researchers said, because they dont carry the risk of generating an immune response. The gene therapy also, ideally, would function as a one-time treatment a therapeutic gift that keeps on giving.

The idea of cell reprogramming is that you express this transcription factor and the cell is then going to convert to this healthier state and stays committed to that healthier phenotype and that conversion is not normally transient, Higuita-Castro said. So in theory, you would not expect to have to re-dose significantly.

There are more experiments to come, testing the effects of other transcription factors that contribute to intervertebral disc development. And because this first study used young adult mice, the team also plans to test the therapys effects in older animals that model age-related degeneration and, eventually, in clinical trials for larger animals known to develop back problems.

Higuita-Castro, director of advanced therapeutics and engineering in the College of MedicineDavis Heart and Lung Research Institute and a core faculty member of Ohio StatesGene Therapy Institute, and Purmessur Walter, an investigator in Ohio States Spine Research Institute and director of the Spinal Therapeutics Laboratory in the College of Engineering, are co-principal investigators on National Institutes of Health grants funding this research.

Additional co-authors include co-first authors Shirley Tang and Ana Salazar-Puerta, Mary Heimann, Kyle Kuchynsky, Mara Rincon-Benavides, Mia Kordowski, Gilian Gunsch, Lucy Bodine, Khady Diop, Connor Gantt, Safdar Khan, Anna Bratasz, Olga Kokiko-Cochran, Julie Fitzgerald and Benjamin Walter, all of Ohio State; Damien Laudier of Icahn School of Medicine at Mount Sinai; and Judith Hoyland of the University of Manchester.

Ohio State has filed a patent application on nonviral gene therapy for minimally invasively treating painful musculoskeletal disorders.

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Gene therapy relieves back pain, repairs damaged disc in mice - The Ohio State University News

Pfizer is preparing to launch its hemophilia B gene therapy Beqvez (fidanacogene elaparvovec-dzkt) after securing a U.S. approval for the treatment last month.

Beqvez is the second gene therapy to be approved for adults with moderate to severe hemophilia B in the U.S., following the clearance of Hemgenix in 2022.

With the U.S. approval of BEQVEZ, physicians and patients now have another choice in the treatment of hemophilia B, Sonal Bhatia, MD, senior vice president and head of U.S. specialty care medical affairs at Pfizer, said in a written Q&A with Hemophilia News Today.

Beqvez is also cleared in Canada and is under review in the European Union.

Bhatia said gene therapies, which directly address the diseases underlying cause, offer transformative potential for long-term bleed control in eligible patients, who are often susceptible to breakthrough bleeds despite being on standard of care preventive therapies.

There is a clear interest and anticipation from the physician and patient community for gene therapy and its potential use alongside conventional treatments, Bhatia said.

Pfizer is focusing on Beqvezs rollout. The therapy is expected to become available by prescription to eligible patients this quarter, Bhatia said.

The company is proactively working with treatment centers, payers, and the hemophilia community to help ensure the healthcare system is appropriately prepared to deliver Beqvez to the patients who can benefit from it, she said.

That includes offering personalized patient support services through Pfizers GeneTogether program. Through the program, patients can access educational materials about what happens before, during, and after receiving gene therapy, and can find help understanding insurance coverage and financial options.

Gene therapies are among the most expensive treatments in the world. Beqvez has a list price of $3.5 million, the same as Hemgenix.

To help ensure that insurance companies are willing to cover the cost, Pfizer is offering a warranty program based on the durability of a patients response, Bhatia said. The program provides financial protection by insuring against the risk of efficacy failure, with the aim of making it easier for patients to access treatment, she said.

Pfizer also offers a co-pay assistance program to help manage out-of-pocket costs for patients who are commercially insured.

Factor replacement therapy has long been the standard prophylactic treatment for hemophilia B. It involves regularly administering infusions into the bloodstream of a working version of factor IX (FIX), the blood clotting protein patients thats faulty or missing due to mutations in the F9 gene that encodes its production.

But despite these treatments, many people living with moderate to severe hemophilia B are at risk of spontaneous bleeding episodes, which can result in painful joint damage and mobility issues, Bhatia said.

This can significantly affect a persons daily life. Bhatia pointed to studies showing that nearly 40% of severe hemophilia patients who are employed experience disease-related restrictions in job performance, and that at least 13% have faced unemployment because of it.

With Beqvez, the hope is to allow people living with hemophilia more time for the things they love and support their ability to engage in the workforce, school, and society, Bhatia said.

The gene therapy, intended as a one-time treatment, provides patients liver cells with a healthy copy of F9. The therapy provides the body with the tools to continuously produce its own FIX protein in the long term, offering lasting bleed prevention.

The potential benefits of Beqvez were demonstrated in the open-label Phase 3 BENEGENE-2 clinical trial (NCT03861273), which tested the effects of the gene therapy in men, ages 18-65, with moderate to severe hemophilia B.

Bleeds were eliminated in 60% of patients after they received Beqvez for up to three years, while only 29% of patients experienced complete bleed control while on standard prophylaxis during a lead-in period prior to receiving the gene therapy.

The overall median annualized bleeding rate was zero after treatment with Beqvez, compared with 1.3 bleeds per year during the lead-in period. The mean annualized bleeding rate dropped from 4.5 bleeds per year while patients were on prophylaxis to 2.5 bleeds per year after receiving Beqvez.

An ultimate goal of gene therapy would be for patients to be less reliant on replacement therapy, or to eliminate it altogether, avoiding years of medical burden, Bhatia said.

Still, the long-term effects of Beqvez, and whether it will offer sustained bleed control for many years, will only be known once treated patients have been followed for a longer period of time.

BENEGENE-2 participants are being followed for up to 15 years: six years in the current study and nine more in a long-term Phase 3 extension study (NCT05568719).

Bhatia said Pfizer is optimistic about the gene therapys long-term safety and efficacy profile.

Patients from an earlier Phase 1/2a trial (NCT02484092) and long-term extension study (NCT03307980) have been followed for up to six years, during which time FIX activity has remained stable, according to Bhatia. With FIX activity generally in the mild hemophilia to normal range, patients have also maintained low bleed rates during that time.

While more long-term data are collected, the company is conducting exploratory modeling analyses aiming to predict the treatments long-term effects based on available clinical trial data.

Results from those analyses presented earlier this year indicated that a one-time infusion was predicted to be efficacious for more than 20 years, maintaining FIX at levels not achievable with recommended replacement therapy dosing. Bhatia said Pfizer will continue to update the modeling analyses as more data become available, adding that the current results are encouraging.

Bhatia touted the recent Beqvez approval as a testament to Pfizers continued effort to advance the standard of care for people living with hemophilia.

The company, which markets a number of approved hemophilia treatments, has other experimental ones in the pipeline. Those include giroctocogene fitelparvovec, a gene therapy for hemophilia A thats in Phase 3 testing, and marstacimab, an injectable therapy currently under review in the U.S. and Europe for hemophilia A and B patients without inhibitors.

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Hemophilia B gene therapy Beqvez offers new choice: Pfizer official - Hemophilia News Today

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"I think the fact that there's so much work going on will create a universe of advanced biological therapies over the next several years, that could become available to more general practitioners and not just in experimental trials."

For clinicians, neurodegenerative disorders present a unique challenge for treatment because of the slow progression of the disease and the profound neuron loss before the onset of clinical symptoms. Options for treatment are additionally constrained by the post-mitotic nature of the central nervous system (CNS) neurons and confined ability of these cells to perform regeneration. Moreover, the blood brain barrier hinders peripheral access to the brain and so there are some limitations inherent in respect to treatment especially for protein and peptide-based therapeutics.1

To combat these constraints, investigators continue to expand the therapeutic platform based on the delivery of genes engineered for efficient CNS expression. Researchers first assessed gene therapy over 20 years ago and since then have continued to evolve it for neurodegenerative diseases like Parkinson disease (PD). Despite incremental advancements realized for PD so far, clinicians believe there is hope for the technology. Gene therapy in PD may offer the opportunity to alter dopamine production and neuronal phenotype permanently, which would be a significant therapeutic advancement even if there isnt a cure found yet.

Michael Kaplitt, MD, PhD, professor of neurological surgery and vice chairman for research in the department of neurological surgery at Weill Cornell Medicine, recently sat down with NeurologyLive in an interview to discuss how gene therapy streamlines the process of developing treatments compared with traditional drug discovery methods. He also spoke about the key factors that would make a patient a suitable candidate for specific gene therapies in neurological disorders. Furthermore, Kaplitt talked about the advancements in gene therapy that are currently being tested for PD.

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The Promising Future of Gene Therapy in Treating Neurological Diseases: Michael Kaplitt, MD, PhD - Neurology Live

A CRISPR-based gene-editing therapy called EBT-101 was safe and well tolerated but did not prevent viral rebound in three participants who stopped antiretroviral treatment in an early study, according to a presentation last week at the American Society of Gene & Cell Therapy annual meeting.

As aidsmap previously reported, researchers presented findings at a conference last October showing that EBT-101 was well distributed in the body and did not cause serious side effects in the first three treated study participants. Although the presentation did not include data about whether the treatment actually worked to control HIV, that didnt stop the Daily Mail from proclaiming that a cure for HIV could be months away one of the many exaggerated claims over the years about the state of HIV cure research.

A unit of heredity, that determines a specific feature of the shape of a living organism. This genetic element is a sequence of DNA (or RNA, for viruses), located in a very specific place (locus) of a chromosome.

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a persons body, or permanently control the virus and render it unable to cause disease. A sterilising cure would completely eliminate the virus. A functional cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness.

A type of experimental treatment in which foreign genetic material (DNA or RNA) is inserted into a person's cells to prevent or fight disease.

But those data are out now, and the news is generally unfavourable. EBT-101 did not maintain HIV viral suppression when used alone at the initial dose tested, though it may have delayed viral rebound in one participant. Also, its good safety profile suggests that similar CRISPR approaches may be feasible for other latent viral infections such as herpes simplex and hepatitis B.

We know that many people were hopeful that a first trial could provide evidence of a possible cure for HIV because the field has been waiting over 20 years for a cure, Excision BioTherapeutics senior vice president Dr William Kennedy said in a news release. However, it was essential that this clinical trial establish safety for EBT-101 as a gene therapy product as well as safety related to the use of CRISPR for the field.

Antiretroviral therapy can keep HIV replication suppressed indefinitely, but the virus inserts its genetic blueprints into the DNA of human cells and establishes a long-lasting reservoir that the drugs cant reach. This integrated HIV DNA lies dormant in resting T cells during treatment, but it can start producing new virus when antiretrovirals are stopped, making a cure nearly impossible. The only way to determine whether an experimental intervention leads to long-term remission is to discontinue antiretroviral therapy with careful monitoring in an analytic treatment interruption.

Professor Kamel Khalili of Temple University in Philadelphia and colleagues have been studying gene therapy with the aim of curing HIV for more than a decade. Their work employs CRISPR/Cas9 sometimes referred to as molecular scissors a technology that combines guide RNAs that home in on specific segments of DNA and a nuclease enzyme that cuts the genetic material at the desired site.

In 2014 and 2016, the researchers reported that a CRISPR/Cas9 tool could cut out HIV genes from CD4 cells in laboratory studies. A study published in 2019 showed that this approach could remove integrated HIV genes and clear latent viral reservoirs in mice. And at the 2019 Conference on Retroviruses and Opportunistic Infections, the Temple University team reported that CRISPR/Cas9 therapy successfully removed segments of an HIV-like virus from viral reservoirs in monkeys.

This research led to the development of EBT-101, a CRISPR-based therapy delivered by an adeno-associated virus vector that uses two guide RNAs to target three sites on the integrated HIV genome. Making cuts at these locations prevents the production of intact new virus. Last August, researchers reported that a single dose of a simian version of the therapy safely and effectively removed integrated SIV in monkeys on antiretroviral therapy. But this study did not include a treatment interruption, so it could not show whether the animals were functionally cured.

The first human clinical trial of EBT-101 (NCT05144386) started in 2022, testing the therapy in people on antiretroviral treatment with a stable undetectable viral load. Excision announced that the first participant in the phase I/II trial received EBT-101 that July, and the study protocol called for participants who maintained viral suppression at 12 weeks after receiving the gene therapy to undergo an analytic treatment interruption.

At last weeks conference, Dr Rachel Presti of Washington University St. Louis School of Medicine provided updated study results. Of the five participants who received a single infusion of the initial dose of EBT-101, three stopped antiretroviral therapy. All three experienced viral rebound and had to restart antiretrovirals. This likely occurred because the gene therapy did not reach all cells harbouring latent HIV, and even a very small number of cells containing residual HIV DNA is enough to re-establish viral replication.

One EBT-101 recipient was able to maintain viral suppression for 16 weeks after treatment discontinuation, considerably longer than it typically takes for the virus to rebound after stopping antiretrovirals. This suggests that EBT-101 or similar CRISPR therapies might one day play a role in a combination cure strategy.

Initial data from the EBT-101-001 trial provides important clinical evidence thatagene editingtreatment modality can be safely delivered fortargetingthe HIV DNA reservoirs in human cells, Presti said. This study provides researchers with invaluable insights for how CRISPR technology can be applied for addressing infectious disease and was an important first step towards additional programs designed to optimize this treatment modality for treating the millions of individuals who are impacted by HIV and other infectious disease.

Excision is now testing a higher dose of EBT-101 in a second cohort and is exploring new CRISPR delivery methods that might be more efficient than the adeno-associated virus vector. One possibility is lipid nanoparticles like the ones used to deliver messenger RNA in COVID-19 vaccines.

Viral rebound likely occurred because the gene therapy did not reach all cells harbouring latent HIV

The company is also exploring CRISPR-based approaches for other latent infections. In other presentations at last weeks meeting, researchers reported promising preclinical results for experimental therapies for herpes simplex (EBT-104) and hepatitis B (EBT-107). Herpes simplex virus (HSV) persists in nerve cells, from which it can reactivate to cause cold sores, genital herpes and keratitis (eye inflammation). Hepatitis B virus (HBV) establishes chronic infection in the liver, where it can lead to cirrhosis and liver cancer. Unlike HIV and other retroviruses, however, HSV and HBV do not integrate their genetic blueprints into the chromosomes of host cells, so they may be easier to remove.

Many lessons have been learned from the small number of people who naturally control HIV, the somewhat larger group of post-treatment controllers and the handful of people who have been cured after stem cell transplants. But for now, a broadly applicable functional cure remains a long-term prospect.

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CRISPR gene therapy EBT-101 does not prevent HIV viral rebound - aidsmap