Molecular Therapy

Prenatal Delivery of a Therapeutic Antisense Oligonucleotide Achieves Broad Biodistribution in the Brain and Ameliorates Angelman Syndrome Phenotype in Mice

Wan Du, MD, PhD - April 11, 2024

Read our monthly summary of a Molecular Therapy article from the April issue of The Vector.

Angelman syndrome (AS), a neurodevelopmental disorder appearing early in life, results from mutations within the 15q11–13 region, with symptoms such as irregular gait, intellectual challenges, and seizures. It impacts multiple genes, with particular emphasis on the imprinted gene UBE3A, responsible for producing the E3 ubiquitin ligase protein 3a (UBE3A). Disruption of the maternal allele of UBE3A leads to impaired neuronal function. This paternal UBE3A suppression is mediated by a nuclear-localized long non-coding RNA called UBE3A antisense transcript (UBE3A-AS). In terms of the early onset of AS, administering therapy to the fetus offers advantages like halting irreversible organ damage, reaching neurons during a phase of heightened blood-brain barrier (BBB) permeability, and promoting tolerance to proteins within the fetal environment. Among various gene therapy techniques, antisense oligonucleotide (ASO) emerges as a safe and efficient strategy for treating a spectrum of disorders, circumventing potential toxicities associated with genomic integration seen in viral vectors. Using a gapmer ASO to degrade the UBE3A-AS transcript can potentially reactivate the intact paternal UBE3A allele, offering a route to genetic rescue for AS.

The authors in this study used a mouse model harboring a Ube3a-YFP allele, which serves as an indicator of ASO activity directed at the intended target, to investigate the safety, distribution in the body, and effectiveness of ASO delivery in utero. They indicated that administering ASOs prenatally through intracerebral (IC) or intra-amniotic (IA) injections leads to extensive delivery to neurons in both the brain and spinal cord. Delivering the ASO in utero, IC injection led to dose-dependent activation of paternal Ube3a. Additionally, in a mouse model of AS, delivering the ASO in utero resulted in the successful restoration of UBE3A levels. Remarkably, systemic biodistribution and significant UBE3A reactivation throughout the brain were also observed following IA injection. The findings of UBE3A restoration throughout the brain holds significant implications for AS patients. The loss of UBE3A impacts neurons across all brain regions, particularly affecting the cortex and hippocampus, leading to profound functional deficits. Therefore, the findings of widespread ASO distribution in the central nervous system (CNS), reinstatement of UBE3A in critical brain regions following both IA and IC injections, along with behavioral improvements during the accelerating rotarod and fear conditioning tests, suggest a promising therapeutic potential in humans. Motor learning impairments, a severe symptom in individuals with AS, are a well-established phenotype in the AS mouse model and are likely linked to cognitive deficits in learning ability. The ASO treatment in the study effectively improved this phenotype and produced behavioral patterns similar to those observed in WT mice, highlighting the potential therapeutic benefits of early ASO administration.

Taken together, this study offers a new approach for early intervention in Angelman syndrome using the ASO, highlighting two potential prenatal administration routes. Moreover, the effective delivery of a therapeutic ASO into neurons extends to implications for developing clinically viable prenatal treatments for various neurodevelopmental disorders beyond AS.

Wan is Junior Editor of The Vector and a postdoctoral research fellow at Mass Eye & Ear/Harvard Medical School.

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