In a groundbreaking Phase I/II clinical trial conducted by UMass Chan Medical School, a dual vector gene therapy for GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff diseases, has shown promising biochemical corrections with minimal adverse reactions. The study marks a significant step forward in the development of treatments for these devastating neurodegenerative disorders.
“Biochemically it worked,” stated Heather Gray-Edwards, DVM, PhD, an assistant professor of genetic & cellular medicine at UMass Chan. “We were able to induce production of the appropriate enzyme and that enzyme was functional. Although we didn’t achieve therapeutic levels, our thalamic injections ended up being safe in patients and the transgene vectors work. That’s an important step.”
Participants in the trial maintained oral feeding for longer periods and experienced fewer, more controllable seizures. These encouraging results, published in Nature Medicine, provide a crucial foundation for further development of treatments for Tay-Sachs, Sandhoff, and other GM2 gangliosidosis diseases. The trial was conducted at UMass Chan and UMass Memorial Medical Center, with Massachusetts General Hospital providing an independent assessment of the clinical impact.
Understanding GM2 Gangliosidosis
GM2 gangliosidosis is a group of inherited disorders, including Tay-Sachs and Sandhoff diseases, characterized by the progressive destruction of nerve cells in the brain and spinal cord. These conditions are often caused by mutations in the HEXA or GM2A gene, which prevent the enzyme beta-hexosaminidase A (HexA) from properly breaking down large molecules inside cells. The deficiency leads to the accumulation of GM2 gangliosides in nerve cells, causing cell damage and death.
Typically presenting in infancy, the disease manifests as slow growth, developmental regression, poor muscle tone, seizures, and loss of motor function. Universally fatal, most children with the disease survive only a few years, although other forms can occur in later childhood, adolescence, or adulthood. Currently, there are no treatments for GM2 gangliosidosis.
Innovative Research and Development
The research led by Gray-Edwards and Miguel Sena-Esteves, PhD, associate professor of neurology at UMass Chan, has been pivotal in advancing the understanding and potential therapies for GM2 gangliosidosis. Their work includes the development of a gene therapy vector to deliver functioning copies of the defective genes causing the disease.
“This research is an example of the important work that our faculty is doing in our Translational Institute for Molecular Therapeutics,” said Terence R. Flotte, MD, the Elisabeth Chair for the Dean of Medicine, executive deputy chancellor, provost, and dean of the T.H. Chan School of Medicine, and senior author on the paper. “Driven by Dr. Gray-Edwards and Dr. Sena-Esteves, the institute leverages our extensive experience in researching and developing gene therapies for early-stage clinical trials so we can play a key role in moving therapies for rare diseases forward.”
The Clinical Trial and Its Findings
In the current study, two harmless viral vectors were administered through injections to the thalamus and spinal cord. These vectors deliver DNA instructions to brain cells, teaching them how to produce the missing HexA enzyme. Once inside the nucleus, the vector-delivered DNA remains in the cells, allowing for long-term enzyme production.
The trial included nine participants in four cohorts, with the dosage doubling for each subsequent cohort. Historically, more than half of patients with GM2 gangliosidosis require IV feeding between 13 and 18 months of age. However, in this study, half of the cohorts maintained full oral feeds for at least 25 months, with the two highest dose participants continuing oral feeds until the end of the study at 27 and 20 months, respectively.
“This is encouraging because eating by mouth is an important quality of life outcome for the families of these children,” said Gray-Edwards.
Clinical tests showed an increase in HexA enzyme production for all participants, with activity surpassing twice the lower limit of normal. Additionally, participants experienced a later onset of seizures, which were less severe, less frequent, and more responsive to anti-convulsant medication.
“Nonetheless, the partial effects of the therapy indicate the need for continued improvements of the gene therapy,” Gray-Edwards noted.
Future Directions and Implications
The next step for Gray-Edwards and the UMass Chan researchers is to modify the dual vector delivery into a single vector. This adjustment would allow for the delivery of double the amount of therapeutic DNA to the cells without increasing the vector volume, a current limiting factor. Such advancements could enable gene therapy treatments to be administered at an earlier age, potentially improving outcomes.
The study received funding from several organizations, including the National Tay-Sachs & Allied Diseases Association, Cure Tay-Sachs Foundation, Matthew Forbes Romer Foundation, and Blu Genes Foundation.
UMass Chan Medical School, a prominent institution within the University of Massachusetts system, is renowned for its contributions to biomedical research and education. The school continues to lead and innovate in the fields of health care delivery and public service, striving to improve health and wellness across diverse communities globally.
