RNA-Directed Therapy for C9ORF72-Linked ALS Using Engineered Zinc Finger Nucleases

Abstract

We demonstrate that an RNA-targeting zinc finger nuclease fusion system (Zl-PIN) eliminates G4C2 RNA expansions in mutant C9ORF72RNA in C9-ALS patient-derived iPSC-derived spinal cord organoids, with minimal transcriptomic off-target effects. We demonstrate that Zl-PIN delivered via an adeno-associated viral vector to the central nervous system of a BAC transgenic mouse model of C9-ALS alleviates signs of neurodegeneration without gross adverse effects, providing proof-of-principle that a member of a new class of zinc-finger RNA targeting effectors can potentially treat C9-ALS, with implications for other neurodegenerative diseases such as frontotemporal dementia.

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Document Details

Document Type
Technical Report
Publication Date
Aug 01, 2023
Accession Number
AD1207977

Entities

People

  • Eugene W Yeo
  • Kathryn M. Morelli
  • Stefan Aigner

Organizations

  • University of California, San Diego

Tags

Communities of Interest

  • Biomedical

DTIC Thesaurus Topics

  • Biological Sciences
  • Biomedical Research
  • Brain
  • Cell Physiological Processes
  • Cells
  • Central Nervous System
  • Dementia
  • Diseases
  • Genetics
  • Indirect Costs
  • Medical Personnel
  • Metabolic Diseases
  • Nervous System
  • Neurodegeneration
  • Neurodegenerative Diseases
  • Parkinson'S Disease
  • Spinal Cord
  • Stem Cells
  • Students
  • Therapy

Fields of Study

  • Biology

Readers

  • Molecular Genetics
  • Molecular and Cellular Biology
  • Traumatic Brain Injury (TBI) and Cognitive Aging in the Guam and Border Populations Affected by Alzheimer's Disease and Tau-Associated Dementias.