Exon-skipping Therapy for ADNP Syndrome

Abstract

Researchers at the University of California, Davis have developed novel antisense oligonucleotide (ASO) therapies that enhance ADNP protein expression to address haploinsufficiency in ADNP syndrome.

Full Description

Activity-Dependent Neuroprotective Protein (ADNP) syndrome is a neurodevelopmental genetic disorder caused by loss-of-function mutations in one allele of the ADNP gene, leading to intellectual disability, developmental delays, autism spectrum features, and multi-systemic symptoms. Current treatments are lacking, prompting the development of antisense oligonucleotides that target upstream open reading frames (uORFs) in the ADNP mRNA 5′-UTR to increase translation efficiency from the healthy allele. By inhibiting translation of uORFs or excluding exon 2 from the mRNA, these ASOs increase ADNP protein levels, potentially improving symptoms. The compositions include chemically modified oligonucleotides designed for stability and efficacy, offering a novel therapeutic avenue for ADNP syndrome.

Applications

• Treatment of ADNP syndrome and related neurodevelopmental disorders. 
• Therapies targeting genetic haploinsufficiency in rare diseases. 
• Precision medicine approaches for autism spectrum disorders with known genetic origins. 
• Pharmaceutical development of antisense oligonucleotide drugs. 
• Potential expansion to other genetic conditions involving uORF-mediated translational regulation.

Features/Benefits

• Increases ADNP protein expression from the healthy allele. 
• Targets uORFs to enhance translation efficiency. 
• Potential to increase ADNP levels by up to 400%. 
• Uses chemically modified oligonucleotides for improved stability and safety.
• Addresses underlying genetic cause rather than symptoms alone. 
• Widely accepted molecular approach with potential for broad applicability. 
• Overcomes the lack of approved treatments for ADNP syndrome. 
• Resolves haploinsufficiency issues related to ADNP gene mutations. 
• Potential to mitigate neurodevelopmental delays and intellectual disabilities associated with ADNP syndrome. 
• Effect is not dependent on differing genetic mutations. 
• Improves safety and compliance compared to previous therapies.

Patent Status

Patent Pending