Angelman syndrome is a rare, genetic disorder, which affects the development of the nervous system. It results in severe developmental delay, balance issues, motor impairment and debilitating seizures. Some individuals with Angelman syndrome are unable to walk and most do not speak. It affects approximately 1 in 12,000 to 1 in 20,000 people globally. Most cases are not inherited, but instead occur spontaneously. With current practices, Angelman syndrome is not routinely detected before or at birth. At this time, there is no approved treatment and individuals are managed with non-specific medication to alleviate symptoms of Angelman syndrome. Affected individuals have a normal lifespan but never become independent adults. The diagnosis has a severe impact on family life, as these individuals need someone to care for them around the clock. Most caregivers must dedicate themselves to the care of their individual diagnosed with Angelman syndrome.
Angelman syndrome is caused by loss-of-function in the maternally inherited allele of the UBE3A gene. People normally inherit one copy of the UBE3A gene from each parent. The maternal-specific inheritance pattern of Angelman syndrome is due to genomic imprinting, a naturally occurring phenomenon in which the maternal UBE3A allele is expressed in the central nervous system but the paternal UBE3A is not. Silencing of the paternal UBE3A allele is regulated by the UBE3A antisense transcript (UBE3A-AS). In almost all cases of Angelman syndrome, the maternal UBE3A allele is either missing or mutated, resulting in limited to no protein expression.
Things that seemed impossible, only a few years ago, are happening today. The first patient in Europe and one of the first in the world was injected with a potential treatment, GTX-102, in a phase I/II clinical trial in Oxford. GTX-102, an investigational antisense oligonucleotide being developed by GeneTx Biotherapeutics and Ultragenyx Pharmaceutical Inc., is delivered via intrathecal administration; it is designed to target and inhibit the expression of UBE3A-AS with the aim to unsilence the paternal UBE3A copy. The trial in Oxford is run by the STRONG research group of the Department of Paediatrics and the MDUK Oxford Neuromuscular Centre led by Professor Laurent Servais. Investigators, families, and the community are excited about the developments for Angelman syndrome in Oxford and look forward to seeing the results of the first of, hopefully, many more trials to come. This is the beginning of a new era for Angelman syndrome, where potential treatments targeting the root cause, the lack of functional UBE3A protein, are reaching the patients’ bedside.
Dr Dora Markati, co-investigator of the trial said: “We are really excited to have dosed the first study participant with a promising potential treatment. Antisense oligonucleotides, genetic therapies really are the future for many more devastating genetic disorders. We are only at the start of a new era in therapeutics!”
The STRONG group with Prof Usha Kini of Genomic Medicine, are simultaneously running a Natural History Study for Angelman syndrome for the first time in the UK, which is generously supported by the Foundation for Angelman Syndrome Therapeutics (FAST) UK. The Natural History Study will contribute to the validation of outcome measures with particular importance for patients and their families and will facilitate clinical trials recruitment. Validated outcome measures and biomarkers are important tools to quantify and prove efficacy in the processes of approval and compensation of new treatments.
The Coordinating Investigator of the trial and Professor in Paediatric Neuromuscular Diseases, Prof Laurent Servais said: “The road before having a treatment for every child with Angelman syndrome in the UK and in the world is still very long, but this is an important first step. The model of a strong collaboration between medical doctors, advocacy groups, and pharmaceutical companies works. We need to continue working together with the same objective: helping these patients and these families!”