The Generative Brain

ADAM8-based gene therapy (Kong, NPDPSC)

The idea is to deliver the gene for ADAM8, an enzyme that cuts the prion protein (PrP) in a way that inactivates it, using a viral vector that crosses into the brain so the brain carries less intact PrP. It is a preclinical project at the National Prion Disease Pathology Surveillance Center at Case Western Reserve University, supported by a 2024 CJD Foundation grant. Unpublished slides show it lowered brain PrP in uninfected mice but did not extend survival in infected mice, while a companion shRNA approach did. No human data exist.

Key facts

  • Mechanism in plain terms: cells normally cut PrP in an alpha-cleavage that gives a neuroprotective N1 piece and a C1 piece that inhibits prion conversion; the lab found ADAM8, a metalloproteinase, is the main enzyme for this cut in muscle cells, so the project tries to raise ADAM8 in brain to cut more PrP.
  • Rationale stated by the grantee: PrP is required for prion replication and pathogenesis yet not needed for life or cell survival, which makes lowering brain PrP attractive.
  • Funding and stage: a 2024 CJD Foundation research grant titled Development of ADAM8-based Gene Therapy for CJD, held at the NPDPSC; the aim is to test an AAV vector carrying a PrP-cleaving enzyme in a well-established CJD mouse model.
  • Developer: Qingzhong Kong, tenured associate professor of pathology and neurology and associate director of the NPDPSC, whose lab says it is still trying to identify the key alpha-cleavage enzyme in brain.
  • Cell evidence: in slides from the lab, AAV-mediated ADAM8 overexpression lowered total PrP by about 96 percent in human neuroblastoma cells.
  • Uninfected-mouse evidence: in the same slides, a single systemic dose of AAV with a blood-brain-barrier-penetrating capsid lowered brain PrP by about 48 to 60 percent in two humanized transgenic mouse lines with no apparent side effects reported; unpublished slides, not peer reviewed.
  • Infected-mouse result: given once at symptom onset to mice infected with sporadic CJD prions, rAAV-ADAM8 did not improve survival (205 versus 204 days in one line, 281 versus 290 days in another, small groups) and the authors suggest ADAM8 may be toxic in infected mice.
  • Companion approach: an AAV-shRNA targeting human PrP, given once at symptom onset in the same model, extended survival by 9.6 percent (216 versus 197 days as stated on the slide); the slide title now pairs ADAM8 with shRNA.
  • Open scientific doubt: the lab's own earlier review notes ADAM8's role in alpha-cleavage appears less prominent in brain neurons than in muscle.
  • Stage limits: no primate, toxicology or first-in-human work was found; the grant description and slides are the only project-specific sources and no peer-reviewed paper on the gene therapy was found as of 2026-10-16.

Timeline

  1. 2012Kong lab reports ADAM8 as the main alpha-cleavage enzyme for PrP in muscle cells (J Biol Chem).
  2. 2024CJD Foundation publishes the 2024 grant record for the ADAM8 gene therapy project.
  3. 2025CJD Foundation grant page last modified.
  4. 2025Kong lab slides on the rAAV-ADAM8/shRNA approach are posted on the foundation site (presentation date unknown).
  5. 2026Searches find no peer-reviewed paper, preprint or registry entry for this gene therapy.
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