ASC Therapeutics and Professor Steven W. Pipe Publish Expert Review on Novel Gene Therapies of Hemophilia A
This publication provides an update of scientific and clinical advances in gene replacement therapies for hemophilia A with focus on:
ASC Therapeutics, a privately held biopharmaceutical company pioneering the development of transformative in-vivo gene replacement, gene editing and allogeneic cell therapies for hematologic, metabolic and other rare diseases announces the peer-reviewed, open-access publication of “Hemophilia A Gene Therapy: Current and Next-Generation Approaches” in Expert Opinion in Biological Therapy1. This publication provides an update of scientific and clinical advances in gene replacement therapies for hemophilia A with focus on:
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Professor Steven W. Pipe, University of Michigan. (Photo: Business Wire)
- Current and next-generation approaches to achieve a safe, durable, and stable transgene expression while avoiding the challenges of factor VIII replacement therapies;
- A thorough review of current and past clinical studies with gene therapies conducted in patients with hemophilia A;
- Addressing the critical role of the viral construct towards decreasing the therapeutic dose and minimizing cellular stress, induction of the unfolded protein response, and the resulting loss of protein production in liver cells;
- Second-generation gene therapies incorporating chimeric DNA sequences in the transgene can increase clotting factor synthesis and secretion, and advance the efficacy, safety, and durability of gene replacement therapy for hemophilia A as well as other blood clotting disorders.
Steven W. Pipe, MD, Professor of Pediatrics and Pathology and Pediatric Medical Director of the Hemophilia and Coagulation Disorders Program at the University of Michigan, and the Principal Investigator of the ASC618 phase 1/2 clinical trial, stated “This comprehensive review summarizes several decades of work of my team and others demonstrating the critical role of cellular stress and the unfolded protein response in the impaired production of clotting factors in the liver. The development of a novel bioengineered construct that has been proven in pre-clinical studies to improve biosynthesis, protein folding, and secretion of factor VIII leads me to predict that in a clinical setting it will reduce therapeutic dosing and increase durability.”
Oscar G. Segurado, MD, PhD, Chief Medical Officer at ASC Therapeutics, added “We are thrilled that the journal Expert Opinion in Biological Therapyhas published this seminal review to inform the medical and scientific community of these exciting developments with gene therapies in hemophilia A. This review describes step-by-step the critical elements required for a durable, safe and effective biosynthesis and production of a clotting factor in liver cells. We strongly believe that learning about the underlying molecular, cellular and protein biology of clotting factor production will advance our competitive edge in the field of liver-targeted gene therapies”.
About Hemophilia A
Hemophilia A accounts for most cases of hemophilia (~80%), affecting approximately 1 of every 5000 live-born males. Over a million people around the world are estimated to have hemophilia, including more than 30,000 in the United States (US)1.
Currently, patients with hemophilia A are managed with prophylactic or on-demand replacement therapy with recombinant FVIII or bypassing agents. The major challenges of current treatment regimens, such the short half-life of hemophilia therapeutics with need for frequent intravenous injections, justify ongoing focus on gene replacement therapies.
About ASC618
ASC618 is an AAV8-based gene therapy for the treatment of hemophilia A, affecting approximately 1 of every 5000 live-born males. ASC618 incorporates a novel liver-specific promoter and a bioengineered, codon-optimized B domain-deleted FVIII variant2; in preclinical studies, ASC618 exhibits at least a 10-fold increase in the biosynthesis and secretion of FVIII compared with native human FVIII bioengineered gene constructs3. ASC618 has the potential to increase durability of clotting factor biosynthesis and secretion by minimizing cellular stress and induction of the unfolded protein response, which may lead to diminished FVIII production from liver cells.
ASC Therapeutics will conduct a phase 1/2 clinical trial to evaluate the safety, tolerability, and preliminary efficacy of ASC618. The program received IND clearance from the U.S. Food and Drug Administration in 2021 and was granted Orphan Drug Designation in 2020. The study design is available at https://www.clinicaltrials.gov/ct2/show/NCT04676048
About ASC Therapeutics
ASC Therapeutics is a biopharmaceutical company pioneering the development of gene replacement therapies, in-vivo gene editing and allogeneic cell therapies for hematological, metabolic and other rare diseases. Led by a management team of industry veterans with significant global experience in gene and cell therapy, ASC Therapeutics is developing multiple therapeutic programs based on four technology platforms: 1) In-vivo gene therapy of inherited blood clotting disorders, initially focusing on ASC618 for hemophilia A, for which U.S. FDA IND clearance was recently obtained; 2) In-vivo gene therapy in metabolic disorders, initially focusing on Maple Syrup Urine Disease, in collaboration with the Universities of Massachusetts and Pennsylvania; 3) In-vivo gene editing, initially focusing on ASC518 for hemophilia A; and 4) Allogeneic cell therapy, with the first indication with a Decidua Stromal Cell-based therapy for steroid-refractory acute Graft-versus-Host Disease. To learn more please visit https://www.asctherapeutics.com/.
References
1 Steven W. Pipe, Gil Gonen-Yaacovi & Oscar G. Segurado (2022) Hemophilia A gene therapy: current and next-generation approaches, Expert Opinion on Biological Therapy, DOI: 10.1080/14712598.2022.2002842
2 Brown HC, Wright JF, Zhou S, et al. Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery. Mol Ther Methods Clin Dev. 2014;1:14036
3 Veselinovic M, Gilam A, Ross A, et al. Preclinical Development of ASC618, an Advanced Human Factor VIII Gene Therapy Vector for the Treatment of Hemophilia A: Results from FRG KO Humanized Liver Mice, C57Bl/6 Mice and Cynomolgus Monkeys. Molecular Therapy 2020;28/4:167-8
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