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  1. Home
  3. Targeted Genome Editing Restores Auditory Function In Adult Mice With Progressive Hearing Loss Caused By A Human Microrna Mutation.
  1. Home
  3. Targeted Genome Editing Restores Auditory Function In Adult Mice With Progressive Hearing Loss Caused By A Human Microrna Mutation.

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Targeted genome editing restores auditory function in adult mice with progressive hearing loss caused by a human

Wenliang Zhu1,2, Wan Du1,2, Arun Prabhu Rameshbabu1,2

  • 1Department of Otolaryngology-Head and Neck Surgery, Graduate Program in Speech and Hearing Bioscience and Technology and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.

Science Translational Medicine
|July 10, 2024

View abstract on PubMed

Summary
This summary is machine-generated.

Genome editing successfully restored hearing in adult mice with a microRNA-96 mutation. This therapy targets the inner ear, offering a potential treatment for dominant deafness-50 (DFNA50).

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Area of Science:

  • Genetics
  • Otolaryngology
  • Molecular Biology

Background:

  • Mutations in microRNA-96 (MIR96) are linked to autosomal dominant deafness-50 (DFNA50), a condition causing delayed-onset hearing loss.
  • While neonatal genome editing shows promise, clinical applications require effective editing in the adult inner ear, which remains largely unexplored.

Purpose of the Study:

  • To develop and evaluate a genome editing therapy for the MIR96 mutation (14C>A) in the adult inner ear.
  • To assess the efficacy and safety of adeno-associated virus (AAV)-mediated delivery of CRISPR-Cas9 for treating DFNA50.

Main Methods:

  • Screening of CRISPR systems and optimization of Cas9 expression and sgRNA scaffold for precise MIR96 mutation editing.
  • AAV delivery of Staphylococcus aureus Cas9 (SaCas9-KKH) and sgRNA to the cochleae of presymptomatic and symptomatic adult Mir96 mutant mice.
  • Development of a dual-AAV system with an AAV-sgmiR96-master targeting all known human MIR96 mutations.

Main Results:

  • Long-term hearing improvement was observed in adult Mir96 mutant mice following AAV delivery of SaCas9-KKH and sgRNA.
  • Efficacy of the genome editing therapy was higher when administered at a younger age (3 weeks vs. 6 weeks).
  • In vivo genome editing demonstrated a favorable safety profile with transient Cas9 expression and no AAV genomic integration in the adult inner ear.

Conclusions:

  • In vivo genome editing using AAV delivery of SaCas9-KKH is effective for long-term hearing recovery in a mouse model of DFNA50.
  • The developed dual-AAV system and optimized sgRNA selection provide a foundation for treating human DFNA50 caused by MIR96 mutations.
  • This strategy holds potential for treating patients with DFNA50, addressing the need for adult inner ear editing.