The hope of genetic therapy

Here’s a quick, up-to-date snapshot of notable ADNP/ADNP-syndrome research (2024–2025):

• Mechanism & biomarkers

  • ADNP loss alters DNA methylation and mitochondrial gene programs in brain tissue; autopsy work provides new mechanistic clues. BioMed CentralPubMed

  • New work suggests unfolded-protein-response (UPR) activation could serve as a severity biomarker and therapeutic readout in ADNP syndrome. (Transcriptomics, 2025.) Tandfonline

  • Practical lab note: a 2024 study warns that some methods fail to detect truncated mutant ADNP protein in patient cells—important for interpreting assays and trial biomarkers. Nature

  • Sex-dependent biology continues to emerge: ADNP is essential for sex-specific hippocampal neurogenesis pathways. PMC

• Therapeutics (preclinical/clinical-adjacent)

  • Renewed interest in davunetide (NAP/CP201)—the ADNP-derived peptide that stabilizes microtubules—includes a 2025 review of intranasal delivery (brain bioavailability highlighted) and 2024 clinical analyses in other tauopathies supporting mechanism and dosing insights. (Note: ADNP-syndrome trials in children are not yet underway as of Aug 2025.) ScienceDirectNature

  • Background: CP201 holds FDA Orphan Drug designation for ADNP syndrome; prior human experience is from other indications (e.g., PSP, MCI). drugdiscoverytrends.comPMC

  • Academic and foundation groups report work toward targeted genetic/RNA approaches (e.g., at UC Davis’s Interventional Genetics Team), though these remain preclinical. adnpfoundation.org

• Natural history & community science

  • Simons Searchlight released 2024 survey/registry updates and a 2025 spotlight PDF (adaptive behavior, seizure history, and comorbidity tracking)—useful for endpoints and trial design. Simons Searchlightcdn.simonssearchlight.org

  • New case series continue to refine genotype–phenotype links and broaden clinical recognition. (2024–2025 reports.) Wiley Online LibrarySpringerLink

• Other research papers available (from UAntwerpen):

  • · D'Incal CP, Van Rossem KE, Cappuyns E, Van Dijck A, Elinck E, De Man K, Scott A, Konings A, Annear DJ, Kooy RF. ADNP Exhibits Methyltransferase Activity in Overexpression Systems and Modulates DNA and Histone Methylation. Autism Res. 2025 Nov;18(11):2174-2191. doi: 10.1002/aur.70132. Epub 2025 Nov 1. PMID: 41174994.

    · D'Incal CP, Van Dijck A, Annear DJ, Harutyunyan L, Elinck E, Dingemans AJM, de Vries BBA, Mateiu L, Meuwissen M, Jansen AC, Kooy RF. A frameshift variant in activity-dependent neuroprotective protein (ADNP) causes nucleocytoskeletal alterations in a dizygotic male twin: a case study. Clin Epigenetics. 2025 Nov 10;17(1):185. doi: 10.1186/s13148-025-01998-7. PMID: 41214838; PMCID: PMC12599069.

    · D'Incal CP, Mateiu L, De Man K, Elinck E, Gozes I, Kooy RF. The ADNP-Mediated Transcriptome Response to Ketamine Impairs the Cytoskeletal Protein Axis. J Mol Neurosci. 2025 Oct 8;75(4):136. doi: 10.1007/s12031-025-02420-w. PMID: 41060476.

    · Harutyunyan L, Kooy RF, D'Incal CP, et al. ADNP-Related Helsmoortel-Van der Aa Syndrome. 2016 Apr 7 [Updated 2025 Aug 21]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355518/

    · D'Incal CP, Cappuyns E, Choukri K, De Man K, Szrama K, Konings A, Bastini L, Van Meel K, Buys A, Gabriele M, Rizzuti L, Vitriolo A, Testa G, Mohn F, Bühler M, Van der Aa N, Van Dijck A, Kooy RF, Berghe WV. Tracing the invisible mutant ADNP protein in Helsmoortel-Van der Aa syndrome patients. Sci Rep. 2024 Jun 26;14(1):14710. doi: 10.1038/s41598-024-65608-x. PMID: 38926592; PMCID: PMC11208605.

    · D'Incal CP, Van Dijck A, Ibrahim J, De Man K, Bastini L, Konings A, Elinck E, Gozes I, Marusic Z, Anicic M, Vukovic J, Van der Aa N, Mateiu L, Vanden Berghe W, Kooy RF. ADNP dysregulates methylation and mitochondrial gene expression in the cerebellum of a Helsmoortel-Van der Aa syndrome autopsy case. Acta Neuropathol Commun. 2024 Apr 18;12(1):62. doi: 10.1186/s40478-024-01743-w. PMID: 38637827; PMCID: PMC11027339.

    · D'Incal CP, Annear DJ, Elinck E, van der Smagt JJ, Alders M, Dingemans AJM, Mateiu L, de Vries BBA, Vanden Berghe W, Kooy RF. Loss-of-function of activity-dependent neuroprotective protein (ADNP) by a splice-acceptor site mutation causes Helsmoortel-Van der Aa syndrome. Eur J Hum Genet. 2024 Jun;32(6):630-638. doi: 10.1038/s41431-024-01556-4. Epub 2024 Feb 29. PMID: 38424297; PMCID: PMC11153555.

    · D'Incal CP, Kooy RF. ADNP in reverse gear. Eur J Hum Genet. 2023 Aug;31(8):849-850. doi: 10.1038/s41431-023-01360-6. Epub 2023 Apr 18. PMID: 37072552; PMCID: PMC10400621.

    · D'Incal CP, Van Rossem KE, De Man K, Konings A, Van Dijck A, Rizzuti L, Vitriolo A, Testa G, Gozes I, Vanden Berghe W, Kooy RF. Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism. Clin Epigenetics. 2023 Mar 21;15(1):45. doi: 10.1186/s13148-023-01450-8. PMID: 36945042; PMCID: PMC10031977.

Genetic therapies like CRISPR-Cas9 gene editing or base/prime editing could be used to correct mutations in the ADNP gene. Since ADNP syndrome is usually caused by a single harmful mutation (most often a truncating mutation), correcting or bypassing that error might restore more normal ADNP protein function. This is conceptually similar to approaches being explored for other single-gene disorders such as Duchenne muscular dystrophy or Rett syndrome.

However, there are major challenges for ADNP therapy. The ADNP gene is unusually large and complex, and it regulates many other genes crucial for brain development, making it a “master regulator.” Editing or replacing it safely is technically difficult. In addition, ADNP syndrome affects the brain very early in development, so timing matters — therapies given later in life may only partially help. Delivering gene therapies across the blood–brain barrier is another big hurdle.

That said, research is moving forward. Some teams are studying drug-based therapies (for example, NAP/CP201, a small peptide derived from ADNP itself) to compensate for the gene’s loss of function. Others are investigating whether RNA-based therapies or future gene editing techniques might eventually be able to correct or bypass ADNP mutations. So while gene editing for ADNP syndrome is not currently available in humans, the field of neurogenetic therapy is advancing rapidly, and it’s an area of hope for families and researchers alike.

Some of these researches are further detailed below