Gene therapy given to children affected by the fatal neurological disorder Tay-Sachs disease is safe and stabilises disease progression, reports an exploratory proof-of-concept study.
Tay-Sachs disease is an inherited neurological disorder caused by mutations in the genes HEXA and HEXB, which encode for the enzyme beta-hexosaminidase A (HexA). In healthy brains, HexA breaks down fat-like molecules called GM2 gangliosides, which otherwise build up to toxic levels. The only effective way to treat Tay-Sachs disease is to restore the HexA enzyme in the brain, yet this is difficult because the blood-brain barrier stops large molecules passing into the brain. However, a team of scientists from the University of Massachusetts Chan Medical School has used genetically modified viruses to get around this problem:
'Our treatment uses two harmless viral vectors to deliver DNA instructions to brain cells that teach them how to produce the missing enzyme. Similar techniques have been used to treat a number of related diseases and other conditions. In the case of Tay-Sachs, these DNA instructions enter the nucleus of these cells and stay there, allowing for long-term production of HexA.', explained senior author Dr Miguel Sena-Esteves in The Conversation.
In this proof-of-concept study published in Nature Medicine, which aimed to assess the safety of the treatment, two girls aged 2.5 years and 7 months, received a one-shot treatment through injections into a central part of the brain and the spine. The scientists chose these sites because they are heavily connected to many other brain regions, which allows the enzyme to travel along these connections and be distributed throughout the whole brain.
The most severe form of Tay-Sachs disease typically manifests within the first year of life with developmental regression, progressive paralysis, and recurrent seizures. There is currently no effective treatment and a life expectancy of less than five years. At the time of publication, the study participants were five and two years old, clinically stable, and showing no or only moderate disease progression. Biochemical analysis suggested that there is a small increase in the patient's HexA activity and that the accumulation of GM2 gangliosides had slowed.
Dr Sena-Esteves believes that better results may be obtained with higher treatment doses: 'More testing is needed to confirm whether our treatment can fully stop disease progression. Given that this was the first time our treatment was given to humans, we used a conservative dose below the maximum therapeutic effects we saw in our animal studies. My colleagues and I are currently conducting a follow-up clinical trial to test the safety and efficacy of increasing doses in a larger number of patients.'
Because Tay-Sachs disease is autosomal recessive, it only manifests if both parents carry the mutation. Consequently, the disorder is very rare in the general population, although its prevalence can be up to ten times higher in communities that practice marriage within a specific group, such as Ashkenazi Jews – who may be more likely to marry within the Jewish community. (see BioNews 658 and BioNews 1024). The low incidence, however, creates additional hurdles with respect to recruiting participants for clinical trials and securing funding for medical research.