We are so grateful to PYC Therapeutics for their informative webinar on PYC-002, an RNA-based gene therapy, held on March 13, 2025, and co-hosted by the Phelan-McDermid Syndrome Foundation and CureSHANK. We encourage you to watch the full webinar and review the Q&A document (both linked below). We also want to provide our PMSF community with a clear breakdown of the key takeaways and next steps!

Important Links

Gene Therapy: “ASO” vs “AAV”?

  • ASO (Antisense Oligonucleotide) Therapy
    • ASOs are synthetic (man-made) form of RNA molecules used in RNA-based gene therapy.
    • ASO therapy targets RNA, making changes reversible—repeat dosing is required to maintain therapeutic benefits.
    • PYC’s approach uses ASOs to help increase production of SHANK3 in the healthy copy of chromosome 22, this is called “SHANK3 upregulation”
    • Injection site: (for PYC-002) Intrathecal (lower spine into the cerebrospinal fluid, or CSF).
  • AAV (Adeno-Associated Virus) Therapy
    • AAV therapy is a gene addition approach that permanently modifies DNA.
    • Only one dose is required for lasting effects.
    • Jaguar Gene Therapy is using AAVs to insert a functional  SHANK3 gene into target brain cells.
    • Injection site: (for Jaguar-201) is unilateral intracerebroventricular (ICV), through the skull into the cerebral ventricles, reaching the cerebrospinal fluid (CSF).

What Has PYC Already Done?

  • Conducted initial studies using Phelan-Mcdermid syndrome patient-derived neurons.
  • Demonstrated an increase in SHANK3 protein production.

What’s Next?

Current Focus: Preclinical Studies

  • Nominating of clinical candidate(s) (an objective marker of ‘success’).
  • Estimated 9-10 months for pre-clinical studies in mouse models and non-human primate models.

Future Plans: Phase 1/2 Clinical Trial in Humans with Phelan-McDermid Syndrome

  • Regulatory submission: Estimated mid-2026.
  • Human Trials: Estimated to begin late 2026/early 2027 (always subject to change).
  • Phase 1: Establish safety.
  • Phase 2: Assess initial efficacy.
  • Trail Design: Initial human trial will be a single-dose trial.

Outstanding Questions

  • Trial Location: Where will initial human clinical trial will occur (Australia vs. United States vs. UK/Europe)?
  • Participant Age Range: What age groups will be included?
  • Trial Size: How many participants will be enrolled?
  • Genetic Inclusion Criteria: Will Class I and Class II deletions be included in the initial trial (PYC indicated it will likely be Class I first, but not definitive)?
  • Treatment Goals: Will the trial target language, cognition, psychiatric/behavior symptoms, etc.?
  • Dosing Plan: How many doses will be needed? What will be the interval between doses?
  • Potential Side Effects: What are the possible risks of treatment?
  • Further Eligibility Criteria: What are the full exclusion/inclusion criteria?

If you have any additional questions, feel free to reach out to PYC at info@pyctx.com or contact Dr. Lauren at lauren@pmsf.org.

Thank you to everyone that participated in this exciting and informative session!