Patients in a clinical phase I / II clinical trial led by the UMASS Chan Medical School of a double vector gene therapy for GM2 gangliosidosis, which includes Tay-Sachs and Sandhoff diseases, presented a biochemical correction of the disease with minimal adverse reactions.
Biochemically, it worked. We were able to induce the production of the appropriate enzyme and this enzyme was functional. Although we have not reached therapeutic levels, our thalamic injections ended up being safe in patients and transgene vectors work. This is an important step. »»
Heather Gray-Edwards, DVM, PhD, Study investigator, Deputy professor of genetic and cellular medicine at Umass Chan
Participants in the trial receiving treatment maintained oral food for longer periods and experienced less and more controllable crises. These results, published in Nature MedicineProvide an important basis for subsequent development of treatment for Tay-Sachs, Sandhoff and other GM2 gangliosidosis diseases. Participants were treated at UMASS Chan and UMASS Memorial Medical Center, while the General Hospital of Massachusetts provided an independent assessment of the clinical impact.
“These are positive stages and Umass Chan is committed to finding a transformational therapy for these children,” said Dr. Gray-Edwards.
GM2 gangliosidosis is a group of hereditary disorders, including Tay-Sachs and Sandhoff diseases, which leads to the progressive destruction of nerve cells in the brain and spinal cord. These conditions are most often caused by a mutation in the HEXAor theGM2AGene, which prevents an enzyme called beta-hexosaminidase a (hexa) from properly decomposing large molecules inside the cells of the body. When this enzyme is deficient, GM2 gangliosides accumulate in nerve cells, causing cellular damage and death. There are several forms of GM2 gangliosidosis, including Tay-Sachs disease, Sandhoff disease and GM2 activator deficiency (AB variant).
The disease is generally in early childhood. During the first months of life, children with disease have slow growth, development regression, poor muscle tone, convulsions and loss of motor function. Universally deadly, most children survive only a few years with the disease, but various other forms of illness can occur in childhood, adolescence or even adulthood. There is no treatments for GM2 gangliosis.
The search for Gray-Edwards and Miguel Sena-Esteves, PHD, Associate Professor of Neurology at UMASS Chan, in the causes and potential therapies for GM2 gangliosidosis, Tay-Sachs and Sandhoff’s diseases has led to important advances in the field, including the development of a vector of gene therapy used to provide feature. defective that cause diseases.
“This research is an example of the important work that our faculty makes in our translation institute for molecular therapies,” said Terence R. Flotte, MD, theElisabeth chair for the dean of medicineChancellor Executive Deputy, Provost and Dean of Th Cha Cha Chab School of Medicine and principal author of the newspaper. “Pushed by Dr. Gray-Edwards and Dr. Sena-Esteves, the Institute takes advantage of our vast experience in the research and development of gene therapies for clinical trials at an early stage so that we can play a key role in moving therapies for rare diseases.
In this study, using a hybrid approach, two harmless viral vectors were administered by injections to thalamus and spinal cord. These vectors provide DNA instructions to brain cells that teach them to produce the missing hexa enzyme. Once inside the nucleus, DNA delivered by the vector remains in cells, allowing long -term production of the enzyme.
The objective for scientists is to provide enough DNA instructions via a viral vector in as many brain cells as possible before the start of the disease with the intention of preventing the death of neurons that cause the disease.
This study included nine participants in four cohorts, the dosage administered dubbing for each cohort.
Historically, more than half of the Patients with GM2 gangliosidosis should be fed via IV between 13 and 18 months. In this study, half of the cohorts remained on complete oral food for at least 25 months, the two highest dose participants remaining on oral food until the end of the study (27 and 20 months respectively).
“This is encouraging because eating through the mouth in an important result of the quality of life of the families of these children,” said Gray-Edwards.
Clinical tests have shown that the production of the HEXA enzyme increased for all participants with an activity twice exceeding the lower limit of normal. In addition, participants later experienced the start of crises, which were less serious, less frequent and more reactive to anti-confectional drugs.
“However, the partial effects of therapy indicate the need for continuous improvement in gene therapy,” said Gray-Edwards.
The next step for Gray-Edwards and Umass Chan researchers is to modify the delivery of the double vector in a single vector. This would allow researchers to double the quantity of therapeutic DNA delivered to cells without having to increase the vector volume, which is a limiting factor. This would also make it possible to deliver gene therapy treatments at an early age, which can also improve results.
The study was partly funded by the National Tay-Sachs & Allied Diseases Association, the Tay-Sachs Foundation Cure, Matthew Forbes Romer Foundation and Blu Genes Foundation.