ASO therapy for adnp

The National Institute of Neurological Disorders and Stroke (NINDS) awarded $395,009 to the University of California, Davis on August 1, 2025, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853). The two-year project, extending through July 31, 2027, supports foundational research to develop antisense oligonucleotide (ASO) therapy for ADNP syndrome (Helsmoortel-van der Aa syndrome), a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, autism spectrum disorder, seizures, and sleep disturbances. The research addresses ADNP syndrome's genetic basis—caused by loss-of-function mutations in the ADNP gene that affects hundreds of genes during development—by investigating whether ASOs can rescue haploinsufficiency by increasing ADNP protein expression.

The project delivers preliminary research data and validation studies supporting subsequent clinical development of the first ASO therapy for ADNP syndrome. Specifically, the research involves two primary deliverables: (1) mechanistic testing of ASOs' ability to increase ADNP protein expression in human neurons derived from induced pluripotent stem cells (iPSCs) by blocking unproductive upstream open reading frames, and (2) characterization of a newly designed humanized ADNP mutant mouse model to establish its utility for preclinical therapeutic evaluation. These foundational outputs are intended to generate translational evidence supporting expanded investigations into precision therapeutics for children with ADNP and related genetic neurological conditions.

Abstract

This proposal will lay the foundation for developing a molecular therapy for adnp syndrome. Also known as helsmoortel-van DER AA syndrome, adnp syndrome is a neurodevelopmental disorder characterized by severe intellectual disability, a myriad of motor dysfunctions, autism spectrum disorder, impaired sensory processing, seizures and sleep disturbances. Adnp syndrome has an incidence of ~1:10,000 live births but accounts for ~0.2% of autism diagnoses, labeling adnp as one of the highest causal risk genes for autism spectrum disorder. Adnp syndrome is caused by mutations in activity dependent neuroprotective protein (adnp), a chromatin modifier that affects over 400 genes during embryonic development and thousands postnatally. The mutations occur DE novo, many of which are heterozygous haploinsufficient loss-of-function (LOF) mutations. This suggests that one approach to therapy could be to rescue the haploinsufficiency by increasing the amount of adnp protein. Through private pilot funding, we have created antisense oligonucleotides (asos) that are able to increase adnp protein expression in ipsc-derived human neurons. The presumed mechanism of action, blocking unproductive upstream open reading frames (uorfs), will be tested in aim 1 of this proposal. Also, because mice do not have the same uorf structure as in human, the ASO cannot be tested in a mouse model. We have therefore designed a fully humanized adnp mutant mouse model. An initial characterization of the molecular features of this model will be investigated in aim 2 of this proposal to demonstrate its utility for adnp therapeutic development. The results of the proposed study should provide foundational preliminary data to support more substantial subsequent studies to create the first ever ASO therapy for adnp syndrome. The results from this study will further advance the translational potential for precision therapeutics for children suffering from adnp and other genetic haploinsufficient disorders.