A dual vector gene therapy for GM2 gangliosidosis, including Tay-Sachs and Sandhoff diseases, has shown biochemical correction of the disease with minimal adverse reactions in a Phase I/II clinical trial conducted by UMass Chan Medical School. The results, published in Nature Medicine, represent an important step forward in developing treatments for these universally fatal neurodegenerative disorders.
"Biochemically it worked," said study investigator Heather Gray-Edwards, DVM, PhD, 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."
Clinical Outcomes Show Promise
The study included nine participants across four cohorts, with administered dosages doubling for each successive cohort. Trial participants demonstrated several encouraging clinical improvements compared to typical disease progression.
Historically, more than half of patients with GM2 gangliosidosis require IV feeding between 13 and 18 months of age. In this study, half of the cohorts remained on full oral feeds for at least 25 months, with the two highest dose participants maintaining 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.
Additionally, participants experienced later onset of seizures that were less severe, less frequent and more responsive to anti-convulsant medication compared to typical disease progression.
Biochemical Markers Show Improvement
Clinical tests revealed that production of the HexA enzyme increased for all participants, with activity surpassing two times the lower limit of normal. This biochemical correction addresses the fundamental deficiency underlying GM2 gangliosidosis, where mutations in the HEXA or GM2A genes prevent the beta-hexosaminidase A enzyme from properly breaking down large molecules inside cells.
When this enzyme is deficient, GM2 gangliosides accumulate in nerve cells, leading to progressive cell damage and death. The disease typically presents in infancy with slow growth, developmental regression, poor muscle tone, seizures and loss of motor function.
Innovative Dual Vector Approach
The gene therapy uses a hybrid approach involving two harmless viral vectors administered through injections to the thalamus and spinal cord. These vectors deliver DNA instructions to brain cells, teaching them to produce the missing HexA enzyme. Once inside the nucleus, the vector-delivered DNA remains in cells, allowing for long-term enzyme production.
The treatment was developed by Gray-Edwards and Miguel Sena-Esteves, PhD, associate professor of neurology at UMass Chan, through research conducted at the Translational Institute for Molecular Therapeutics.
Future Development Plans
"Nonetheless, the partial effects of the therapy indicate the need for continued improvements of the gene therapy," said Gray-Edwards.
The next step involves modifying the dual vector delivery into a single vector system. This approach would allow researchers to double the amount of therapeutic DNA delivered to cells without increasing vector volume, which represents a current limiting factor. The single vector approach would also enable gene therapy treatments at an earlier age, potentially improving outcomes.
"These are positive steps forward and UMass Chan is committed to finding a transformational therapeutic for these children," said Gray-Edwards.
The study was funded in part by the National Tay-Sachs & Allied Diseases Association, Cure Tay-Sachs Foundation, Matthew Forbes Romer Foundation and Blu Genes Foundation. Participants were treated at UMass Chan and UMass Memorial Medical Center, while Massachusetts General Hospital provided independent clinical impact assessment.
