This article was written by Dr Keith Mayl and Dr Ahmad Al Khleifat of King’s College London.
Researchers at King’s College Hospital, led by Professor Christopher Shaw, have embarked on the first gene therapy clinical trial for patients affected by a specific genetic form of ALS, the most common type of MND.
ALS is a progressive disease in which the nerves controlling muscle movement, known as motor neurons, degenerate resulting in muscle wasting and weakness. In about 10% of people the cause is a mutation in the C9orf72 gene. This mutation results in the formation of toxic products which are harmful to motor neurons. People with the mutation typically develop symptoms in their 50s, starting with speech and swallowing problems, followed by weakness of the arms, legs and breathing. It is also linked to problems with language and behaviour and is the most common genetic cause of frontotemporal dementia.
Currently, no cure for ALS exists. In 2006 two international groups of researchers led by Professor Christopher Shaw and Professor Ammar Al-Chalabi, both at King’s College London, first narrowed the location of the mutation to a region on chromosome 9. By 2010 Professor Al-Chalabi’s team, working with collaborators worldwide, was able to show that just one of three genes must be the culprit. Eventually the responsible mutation was discovered to be in the C9orf72 gene, and this is now known to be the most common genetic cause of ALS. Since the mutated gene produces toxic products, blocking the gene with gene therapy might be a useful approach to treatment. A phase 1 clinical trial using a novel gene therapy developed by leading pharmaceutical company Biogen, in collaboration with Ionis Pharmaceuticals Inc., is now underway to test this idea.
The gene therapy is a short DNA molecule called an antisense oligonucleotide (ASO) which is capable of selectively binding to and degrading toxic products made from the C9orf72 mutation. The ASO is delivered by injection directly into the fluid which surrounds the brain and spinal cord by inserting a thin needle into the lower spine through a technique called lumbar puncture. The clinical trial is taking place across multiple sites in the USA, Canada and Europe. The aim is to recruit up to 80 patients to take part in this multiple-ascending-dose study to test the safety and tolerability of the ASO. It is currently scheduled to run until 2021 and will aim to test up to 6 cohorts of patients at different doses.
The first dose for the study at King’s College Hospital was successfully delivered by Dr Keith Mayl on Monday 16th September 2019. This is the first gene therapy for a neurodegenerative disease to be trialled in patients at King’s College Hospital. It is a key moment for the motor neuron disease community and if the therapy is successful, will have wider implications for neurodegenerative diseases.
Those wishing to know more about this study and potential recruitment can visit the clinical trial website.