Preliminary Results from Gene Therapy in Tay-Sachs Disease Patients

Terence R. Flotte, MD, Provost and Executive Deputy Chancellor of the University of Massachusetts Medical School, discusses a phase 1 clinical trial evaluating an AAV gene therapy in patients with Tay-Sachs disease.
Tay-Sachs disease is a rare neurodegenerative disease caused by mutations in the HEXA gene. Mutation of this gene leads to a deficiency of the enzyme, beta-hexosaminidase A, which is needed to break down GM2 ganglioside. This leads to build-up of GM2 ganglioside in neurons. In general, the less beta-hexosaminidase A (HexA) a Tay-Sachs patient has, the more severe the disease and the earlier that symptoms appear. The most common symptoms of Tay-Sachs disease are gradual loss of skills, seizures, and loss of muscle and cognitive functions.
Currently there are no targeted therapies approved for Tay-Sachs disease. Recently, however, promising initial results were published in the journal, Nature Medicine, from a phase 1 clinical trial evaluating AXO-AAV-GM2.
AXO-AAV-GM2 is an investigational gene therapy that uses a combination of AAVrh8-HEXA and AAVrh8-HEXB vectors. This theoretically would allow the gene therapy to be used as a treatment for both Tay-Sachs disease and Sandhoff disease, the latter of which is caused by a mutation in the HEXB gene therapy.
As Dr. Flotte explains, data was presented about 2 patients with infantile Tay-Sachs disease who received AXO-AAV-GM2 during the first stage of this 2-stage clinical trial. The first patient showed signs of developmental delay at 5-6 months and was dosed at 30 months (total dose, 1 × 1014 vector genomes (vg), administered intrathecally). The second patient was clinically well at enrolment but had two older siblings who presented with developmental delay around 7 months. This patient was dosed at 7 months by combined bilateral thalamic (1.5 × 1012 vg per thalamus) and intrathecal infusion (3.9 × 1013 vg).
In general, injection procedures were well tolerated, with no vector-related adverse events to date. In both patients, cerebrospinal fluid HexA activity increased from baseline and remained stable.
The first patient remains seizure-free at 5 years of age on the same anticonvulsant therapy as before therapy. According to Dr. Flotte, this patient’s condition has stabilized without further disease progression, and though she has developmental delay, she is able to interact with her younger brother.
Information about the second patient is less known, though compared to her older siblings with Tay-Sachs, she has been less impacted by the disease, according to Dr. Flotte. This patient had partial disease stabilization and developed anticonvulsant-responsive seizures at 2 years of age.
Overall, the first stage of this study provides early safety and proof-of-concept data in humans for the use of AAV gene therapy in patients with Tay-Sachs disease.
Based on the above results, a second stage of the study has become. Dr. Flotte stated they have dosed five additional patients with AXO-AAV-GM2. Neurologic function was first evaluated in patients before they were put on immunosuppressants 2 weeks prior to the infusion of AXO-AAV-GM2 via deep-brain and intrathecal injection. Follow-up treatment is primarily outpatient though patients will be routinely brought into Massachusetts General Hospital for evaluation.
To learn more about Tay-Sachs disease and other rare neurological disorders, visit checkrare.com/diseases/neurol...

[@messimagisterial4216]

This is a big step in the field of research to tackle this issue. These are very impressive results in tackling Hexosaminidase A deficiency.

[@anilkumarns7208]

Hello, Is there anyway we can get in touch with the doctor in the video above or hospital details to discuss about our son’s case. Please Help!!!

[@naifal-ghamdi483]

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[@sssg966]

@@naifal-ghamdi483
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[@histologie9820]

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[@histologie9820]

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[@ashantiafricana9559]

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[@shovaniraula9066]

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