FAST UK Supported Research: Therapies in Development
From FAST UK
FAST UK is very proud to have supported this research into Angelman Syndrome therapies in preclinical and clinical development. Dora Markati together with her co-authors Jessica Duis and Laurent Servais have critically assessed the academic literature as well as non-peer-reviewed publications and presented a valuable snapshot of the landscape.
The article titled “Therapies in preclinical and clinical development for Angelman syndrome ” has now been accepted by the Expert Opinion on Investigational Drugs.
Theodora Markati, Jessica Duis & Laurent Servais (2021) Therapies in preclinical and clinical development for Angelman syndrome, Expert Opinion on Investigational Drugs, DOI: 10.1080/13543784.2021.1939674
Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase E3A, known as UBE3A, in the central nervous system. There is no disease-modifying treatment available, but the therapeutic pipeline of Angelman syndrome includes at least 15 different approaches at preclinical or clinical development. In the coming years, several clinical trials will be enrolling patients, which prompted this comprehensive review.
We summarize and critically review the different therapeutic approaches. Some approaches attempt to restore the missing or nonfunctional UBE3A protein in the neurons via gene replacement or enzyme replacement therapies. Other therapies aim to induce expression of the normal paternal copy of the UBE3A gene by targeting a long non-coding RNA, the UBE3A-ATS, which interferes with its own expression. Another therapeutic category includes compounds that target molecular pathways and effector proteins known to be involved in Angelman syndrome pathophysiology.
We believe that by 2022–2023, more than five disease-modifying treatments will be simultaneously at clinical testing. However, the are several challenges with regards to safety and efficacy, which need to be addressed. Additionally, there is still a significant unmet need for clinical trial readiness.
- Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder, which is caused by deficiency or abnormal function of the maternal, ubiquitin protein-ligase E3A, known as UBE3A protein in the central nervous system.
- Several molecular mechanisms, including deletions and mutations, can affect the maternal UBE3A gene on chromosome 15 and subsequently expression of a normal protein. The paternal copy of the gene is silenced in neurons by genomic imprinting. A long non-coding RNA, the UBE3A-ATS is believed to hinder expression of the normal paternal UBE3A gene.
- Among the therapeutic strategies in the AS pipeline are those approaches that aim to restore the missing or non-functional UBE3A protein in the neurons via gene replacement or enzyme replacement therapies. An adeno-associated virus-mediated gene replacement therapy is in late preclinical development, close to clinical testing.
- Another promising category of therapeutic approaches for Angelman Syndrome is targeting the UBE3A-ATS transcript intending to ‘unsilence’ the paternal UBE3A gene. This category includes, among other, antisense oligonucleotides, topoisomerase inhibitors, and genome engineering approaches. Two antisense oligonucleotides are currently in clinical trials with a third one following.
- Other therapeutic approaches are targeting downstream molecular pathways, known to be involved in Angelman Syndrome pathophysiology.
- More than 15 therapeutic approaches with the potential to treat Angelman Syndrome are currently at preclinical and clinical development stages. There is still no available disease-modifying treatment for Angelman Syndrome. However, we believe that in the next few years several candidates will be in clinical development simultaneously for Angelman Syndrome.