The clinical trial, published by T. R. Flotte, together with H. L. Gray-Edwards, and M. Sena-Esteves on Nature Medicine highlighted the promising results obtained by the gene therapy for Tay-Sachs disease applied to two human patients.
Tay-Sachs Disease (TSD) is an inherited neurological disease caused by mutations in two genes (HEXA and HEXB) fundamentals for the metabolism of gangliosides, glycolipids particularly abundant in the neuronal cells. The inactivity of the two enzymes results in the accumulation of gangliosides, which eventually lead to the destruction of nerve cells in the brain and spinal cord.
In the infantile TSD, the most common form, the activity of the two enzymes is less than 0.1% compared to the normal ones. The diagnosis usually occurs in the first 12–14 months of life, when the baby gradually loses the ability to turn over, sit or crawl. Other symptoms include the progressive loss of acquired developmental milestones, seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. To date, the treatments for TSD are only supportive, highlighting the need for effective treatments.
The most important issue in this novel gene therapy was in the administration of the treatment: in this type of disease, the therapy must be widely spread across the central nervous system. For this reason, the two TSD patients were treated with a combination of adeno associated viral vectors (AAVrh8-HEXA e AAVrh8-HEXB) to favor the delivery both to the thalamus and to the cerebrospinal fluid.
The first patient received the treatment at two years old, in a stage of advanced symptoms. Even if in the first months after administration no significant change in the symptoms was detected, to date, at 5 YO, the patient shows no seizures (the most frequent symptoms before the therapy), together with the amelioration of the vision and the improvement of several body mass parameters. The second patient received the treatment at 7 months old. The therapy was able to ameliorate cerebral development, and, to date, seizures have been overcome. For both the patients, the obtained results showed a slight increase in the activity of HEXA in the cerebrospinal fluid.
Considering these results, the success of this gene therapy appears evident. The achievements are even greater if we considered that the gene therapy was performed on patients showing important symptoms and that the pandemic greatly decreased the data availability.
Even if other clinical trials and other investigations are needed in order to better characterize the efficacy, the dose-response, and the possible side effect of this therapy, the success of this treatment can be considered as further proof of the efficacy and safety of the gene therapy and ATMPs in general.