Neurodevelopmental disorders (NDDs) are one of the most common presentations among all genetic conditions. With the exciting development of molecular based therapies such as gene therapy, antisense oligonucleotides (ASO), and CRISPR gene editing, it is anticipated that many of these treatments will be in different stages of preclinical and clinical trials within the next decade.  One of the interesting and most important questions is the reversibility of ND impairments after postnatal correction of genetic defects, particularly in conditions that are nondegenerative.  

In this scientific session we would like to illustrate the successful strategy, questions answered, and challenges faced in the development of a robust therapeutic pipeline for the rare monogenic nondegenerative NDD, Angelman syndrome (AS). AS is a severe neurogenetic disorder caused by the maternal deficiency of UBE3A gene in the 15q11-q13 imprinting domain. UBE3A is a maternal and brain specific imprinted gene that is exclusively expressed in brain from the maternal chromosome. The paternal copy of UBE3A is structurally intact and silenced by a paternally expressed antisense non-coding RNAs of UBE3A (UBE3A-ATS). The inactivation of UBE3A-ATS by small molecules, ASOs, miRNA, Artificial Transcription Factors, and CRISPR-Cas9 editing during different stages of brain development result in the reactivation of UBE3A from the silenced paternal chromosome and each have demonstrate a partial or complete rescue of neurobehavioral impairments in the highly characterized AS mouse model. In addition, AAV-gene therapy, ex-vivo hematopoietic stem cell replacement, enzyme replacement and CRISPR-activation are all being advanced toward the clinic. The age of gene replacement or paternal gene activation in these models shows contradicting results, arguing against a true therapeutic window of intervention.   The patient advocacy group, the Foundation for Angelman Syndrome Therapeutics (FAST), has supported each of these programs from discovery, through proof-of-concept- and now many into IND-enabling studies for First-in-Human (FIH) clinical trials for AS. In doing so, they founded a company, GeneTx Biotherapeutics, who advanced the first disease-modifying therapy, an ASO, into a Phase 1/2 clinical trial in 2020, which was recently acquired by Ultragenyx Pharmaceuticals. The positive interim data from this trial, albeit open label in 74 participants has demonstrated promising findings with the largest improvements in cognition, communication, sleep and adaptive behaviors in children aged 4-17 years.  These encouraging results touch on one of most interesting questions in human neurobiology: how plastic is the human brain during development postnatally and is there a therapeutic window in which improvement for brain disorders can no longer occur?  Can gene restoration treatment reverse ND impairments? The announced phase 3 clinical trial for 4-17 year old AS may be one of the first NDDs to provide answers to this fundamental question. 

This proposed scientific session will highlight the robust drug development process taken on for AS, the role the patient advocacy group (FAST) and how their ability to de-risk programs exploded the field, the success of the first ASO therapy to get to FIH, lesson learned from ongoing ASO clinical trials, the progress of the NIH supported gene editing project, and debate about brain plasticity for the gene correction treatment for AS and more broadly for all monogenic NDDs.