- First known bovine model used to demonstrate safety and efficacy in gene replacement therapy
- MSUD is a severe genetic disease with liver transplantation or dietary restriction as the only treatments currently available
MILPITAS, Calif.–(BUSINESS WIRE)–#ASCCT22–ASC Therapeutics in partnership with the University of Massachusetts Medical School (UMMS) and the Clinic for Special Children (CSC), will present safety and efficacy results of a dual-function gene replacement vector therapy in murine and bovine models of classic Maple Syrup Urine Disease (MSUD) as a podium presentation on Tuesday, May 17 (Room 201, 3:45 PM – 4:00 PM ET, abstract number: 461) at the 25th Annual Meeting of The American Society of Gene and Cell Therapy (ASGCT) held May 16-19, 2022 in Washington D.C.
The research group at UMMS, led by Guangping Gao, PhD, director of the Horae Gene Therapy Center at UMMS, and Dan Wang, PhD, assistant professor of RNA therapeutics, developed murine and bovine models for MSUD with collaborating clinical expert, Dr. Kevin Strauss, MD, from the Clinic for Special Children.
Three animal models were generated to test safety and efficacy: two murine models representing two common genetic forms of MSUD and a newborn calf naturally homozygous for a mutation that causes MSUD. All animals exhibited severe biochemical abnormalities hours after birth and die within 10 days if left untreated.
The partnership designed a dual-function AAV9 gene replacement vector that was administered via intravenous (IV) injection. Surviving mice grew and behaved similar to normal littermates and had normal or nearly normal biochemical markers with unrestricted diet for 16 weeks.
As compared to MSUD patients, MSUD calves exhibit a similar phenotype and are closely matched for size and metabolic rate. Without treatment they exhibit cerebral edema by day of life 3 and die soon after. In October 2021, a MSUD calf was born and developed biochemical signs of MSUD shortly after birth. The calf was administered the AAV9 gene therapy vector at 40 hours of life. Following AAV therapy, biomarker measurements indicated a significant restoration of the missing enzymatic activity. At 70 days after treatment, the calf was transitioned to a normal unrestricted diet and continues to thrive 100 days post-infusion with stable biochemical markers.
These data provide early demonstration of the safety and efficacy of the MSUD AAV9 gene therapy replacement vector as a one-time treatment for the most common and severe forms of MSUD.
“The MSUD gene therapy development leverages the combined AAV gene therapy expertise at UMass Chan Medical School, such as AAV vector design, rodent and large animal modeling, large-scale vector production, and in vivo pre-clinical testing,” Drs. Gao and Wang commented.
Dr. Kevin Strauss, MD, Medical Director at the Clinic for Special Children in Pennsylvania, a collaborating clinical expert, added, “An innovative collaboration between the Clinic for Special Children and UMMS Horae Gene Therapy Center has allowed us to thoughtfully streamline the process of developing AAV gene replacement vectors. Within just three years of project inception, we have safely corrected an otherwise fatal MSUD phenotype in both mice and a newborn calf using a novel dual-function BCKDHA-BCKDHB vector, which has the potential to address 70-80% of reported MSUD cases in humans. The newborn calf with MSUD may represent the largest non-human experimental animal ever treated with AAV-mediated gene replacement. The calf provides unique insights that can directly inform the design of a clinical trial, which we hope to pursue through an alliance with ASC Therapeutics.”
Dr Ruhong Jiang, CEO at ASC Therapeutics, said, “The significant progress achieved through our research collaboration with Professors Gao, Wang and Strauss underlines the intrinsic value of bringing together teams from academia and industry that are highly specialized in complex gene therapies.”
About Maple Syrup Urine Disease
Maple syrup urine disease (MSUD) is a rare genetic disorder affecting degradation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine and their ketoacid derivatives. MSUD is caused by biallelic mutations in one of three genes that encode subunits of the branched-chain ketoacid dehydrogenase complex (BCKDC), namely BCKDHA, BCKDHB, and DBT. Dietary BCAA restriction is the mainstay of treatment but has insufficient efficacy, and affords no protection against episodic and life-threatening encephalopathic crises. Severe (‘classic’) MSUD is fatal without treatment. MSUD affects approximately 1 per 185,000 births worldwide.
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, a second generation gene replacement treatment for hemophilia A; 2) In-vivo gene therapy in metabolic disorders, initially focusing on Maple Syrup Urine Disease; 3) In-vivo gene editing, initially focusing on ASC518 for hemophilia A; and 4) Allogeneic cell therapy, initially focusing on a Decidua Stromal Cell-based therapy for steroid-refractory acute Graft-versus-Host Disease. To learn more please visit https://www.asctherapeutics.com/.
About the Clinic for Special Children
The Clinic for Special Children (CSC) is a non-profit organization located in Strasburg, PA, which provides primary care and advanced laboratory services to those who live with genetic or other complex medical disorders. Founded in 1989, the organization provides services to over 1,200 individuals and is recognized as a world-leader in translational and precision medicine. The organization is primarily supported through community fundraising events and donations. For more information, please visit www.ClinicforSpecialChildren.org
About the University of Massachusetts Medical School
The University of Massachusetts Medical School (UMMS), one of five campuses of the University system, is comprised of the School of Medicine, the Graduate School of Biomedical Sciences, the Graduate School of Nursing, a thriving research enterprise and an innovative public service initiative, Commonwealth Medicine. Its mission is to advance the health of the people of the Commonwealth through pioneering education, research, public service and health care delivery with its clinical partner, UMass Memorial Health Care. In doing so, it has built a reputation as a world-class research institution and as a leader in primary care education. For more information, please visit https://umassmed.edu/
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Steve Zhang
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