Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.
The most important CYFIP1 overexpression paper. Shows CYFIP1 duplication in mice causes enlarged dendritic spines, mTOR hyperactivation, and behavioral abnormalities — all rescued by rapamycin. The foundational mechanistic evidence for rapamycin as a near-term treatment.
CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders.
Shows CYFIP1 overexpression and deletion produce opposite NMDA receptor effects — overexpression causes NMDA hypofunction. This is the mechanistic basis for D-cycloserine as a treatment: restoring NMDA co-agonist activity to compensate for hypofunction.
New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes.
Mechanistic study of CYFIP1 in both WAVE complex (actin regulation) and FMRP complex (mRNA translation). Explains why CYFIP1 overexpression disrupts two separate pathways simultaneously — actin dynamics AND synaptic protein synthesis — both downstream of mTOR.
15q11.2 microdeletion/microduplication at the BP1-BP2 region: a susceptibility locus for neurological and psychiatric disorders.
The foundational paper defining the 15q11.2 BP1-BP2 region as a susceptibility locus. First systematic description of the clinical phenotype of carriers — both deletion and duplication. Essential reference for any clinical discussion of this diagnosis.
Reversal of phenotypes in MECP2 duplication mice using genetic rescue or antisense oligonucleotides.
The single most important analog paper. MECP2 duplication (too much MeCP2 protein) is the closest existing model to CYFIP1 duplication. This paper used ASOs to reduce MECP2 expression in mice and patient iPSC neurons — reversing the phenotype. This result directly enabled the ATTUNE clinical trial (NCT06430385) now running. The CYFIP1 program would follow the identical pathway.
Angelman syndrome patient-derived neuron screen leads to clinical ASO rugonersen targeting UBE3A-ATS with long-lasting effect in monkeys.
Full disclosure of rugonersen — the Roche clinical ASO candidate for Angelman syndrome, same chromosome 15q. Shows how patient-derived neuron screening identified the clinical candidate. Expanded Access program now open (NCT07136454). The most advanced ASO program on chromosome 15 — directly maps the regulatory and manufacturing path for a CYFIP1 ASO.
Emerging disease-modifying therapies for Angelman syndrome: ASOs, gene therapy, and epigenetic editing.
Comprehensive 2026 review of the full therapeutic pipeline for chromosome 15q — ASOs (three now in Phase 3), gene therapy, CRISPR. Directly maps to the CYFIP1 therapeutic roadmap. Useful reference for neurologist consultations.
Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing (CRISPRoff).
The CRISPRoff paper — dCas9-DNMT3A-KRAB fusion that silences any gene via CpG methylation without altering DNA sequence. Heritable, reversible, highly specific across 20,000 tested targets. This is the core technology for the CYFIP1 epigenetic silencing approach — targeting the CYFIP1 promoter to reduce expression from ~150% to ~100%.
A xenotransplantation model for reactivation of paternal UBE3A using human-specific antisense oligonucleotides.
Erasmus MC xenotransplantation platform — human iPSC-derived neurons transplanted into neonatal mouse brain, then ASO delivered by ICV injection to test human-specific sequences in a living brain. This is the testing platform for a CYFIP1 ASO. Erasmus MC (Prof. Elgersma's institution) has this operational now — directly relevant to the sponsored research agreement strategy.
Nickase NmCas9 unsilences paternal Ube3a in a mouse model of Angelman syndrome without causing AAV vector integration.
NmCas9 (Neisseria meningitidis Cas9) delivered via AAV9 — smaller than SpCas9 (~3.2kb), fits in a single AAV9 vector, reaches ~87% of cortical neurons for >6 months without DNA double-strand breaks or AAV integration. This is the delivery vehicle for the CYFIP1 dCas9-DNMT3A epigenetic silencing approach. Mark Zylka (UNC) is a key contact for the CYFIP1 program.
SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients.
iPSC-derived neurons from Phelan-McDermid (SHANK3) patients treated with IGF-1 — showed partial synaptic restoration in the dish. This iPSC result directly led to the IGF-1 Phase 2 clinical trials now running for SHANK3 autism. Classic example of the pipeline: patient neurons → drug works in dish → clinical trial.
Reversal of disease phenotypes in SYNGAP1 haploinsufficiency using lovastatin.
SYNGAP1 iPSC neurons showing ERK hyperactivation, treated with lovastatin in the dish — rescued. Phase 2 lovastatin trial now recruiting (NCT05765734). Another clear example of the patient neuron → drug screen → trial pipeline that the CYFIP1 program will follow.
ASO therapy for the CNS: from nusinersen to the next generation of intrathecal oligonucleotides.
Comprehensive review of intrathecal ASO delivery to the CNS — the delivery platform that will be used for a CYFIP1 ASO. Covers nusinersen (SMA), the regulatory pathway, safety monitoring, dosing, and the evidence base for intrathecal delivery to neurons. Essential background for any IND discussion.
Note on paper access: Most papers link to PubMed. Papers in PMC (PubMed Central) are freely accessible — look for the PMC link. For paywalled papers, your university or hospital library will have access, or email the corresponding author directly — researchers typically provide PDFs on request.
Papers marked with PMC link are freely downloadable.