Surupa Chakraborty, Amity University Kolkata
A new gene therapy clinical trial for treating Angelman syndrome has been put to hold after two candidates temporarily lost their ability to walk. GTX102, the drug used in the clinical trial was developed by a California-based biopharmaceutical company Ultragenyx, in collaboration with GeneTx, a Florida-based biotech startup. The trial was launched in February to analyse the efficacy and safety of a novel therapy for treating the rare autism-linked condition. In a recent trial report, it was revealed that five individuals, aged 5 to 15, were directly administered with GTX102 once a month for over four months. However the dosage varied for all, two were given the lowest dose, two others were given the second-lowest dose and one was given the second-highest dose.
The candidates started experiencing adverse effects and developed symptoms within one to four weeks after taking the highest dose. Two of them were unable to walk and the side effects appeared as a result of nerve inflammation which was probably due to the accumulation of the drug in that area. Based on the striking shreds of evidence of the safety trial, the researchers concluded that antisense oligonucleotides can produce toxic effects if administered at high concentrations. The candidates recovered after receiving drugs that decreased the inflammation and showed significant improvements in multiple traits, including neuromotor skills, communication and sleep.
Angelman syndrome is a rare neurodevelopmental condition associated with severe intellectual disability, autism, seizures, neuromotor problems, sleeping and eating difficulties etc., that affects one in about 12,000 people. It occurs due to a missing or mutated copy of the UBE3A gene which codes for a protein beneficial for healthy brain activity. Normally people inherit two copies of the gene from each parent, but the paternal copy remains silent. However, in people with Angelman syndrome, the maternal copy of the gene has a small mutation or is completely absent, and no protein is produced.
Recently, researchers found this novel approach to treat the disorder by using snippets of RNA that bind to DNA, thereby activating the silent copy of the UBE3A gene. This in turn had successfully reversed the abnormal motor activity, anxiety and memory associated problems in mice. The companies are clear-eyed about the challenges and are currently working on limiting the maximum dosage range within which the drug will render necessary improvements without causing any severe side effects. This therapeutic approach can pave the way to the development of many such gene therapies aimed at boosting the silent protein in neurodevelopmental disorders like Angelman syndrome and can serve as a benchmark in future clinical trials.
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