Yale University has received a USD 3.5 million NIH supplement award to advance a non-viral CRISPR delivery platform toward a first-in-human Phase I safety trial in Angelman syndrome (AS) and H1-4 syndrome, two severe neurodevelopmental disorders with no approved disease-modifying therapies.
The award, administered by the National Center for Advancing Translational Sciences (NCATS) under the Somatic Cell Genome Editing (SCGE) program, funds investigators Jiangbing Zhou, Yong-Hui Jiang, and Elizabeth Mara Berry-Kravis across Yale and Rush University. The supplement covers the period August 2026 through July 2027.
The platform centers on a chemically modified ribonucleoprotein (cRNP) system delivered intrathecally to achieve broad neuronal distribution throughout the brain. In AS, the approach targets UBE3A-antisense transcript (UBE3A-ATS), a non-coding RNA that silences the paternal copy of UBE3A; CRISPR-mediated disruption of UBE3A-ATS is intended to de-repress paternal UBE3A expression. In H1-4 syndrome, a gain-of-function disorder caused by a frameshift mutation in the histone H1.4 gene, the same platform is used to knock down the aberrant transcript. Preclinical data in validated mouse models, the team reported, demonstrated correction of neurobehavioral phenotypes following a single intrathecal dose.
Current AS clinical programs rely on antisense oligonucleotides (ASOs), which require repeated dosing due to transient effect. Three Phase I/II ASO trials are ongoing. The non-viral delivery format differentiates Yale's platform from AAV-based gene editing approaches by delivering the CRISPR machinery transiently rather than relying on persistent viral-vector expression, potentially reducing immunogenicity and prolonged Cas9 exposure. If the approach translates beyond these initial indications, the broader significance could lie in establishing a reusable non-viral platform for delivering genome-editing machinery to neurons throughout the CNS.