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Dose-Dependent Effects of FKRP Gene-Replacement Therapy on Functional Rescue and Longevity in Dystrophic Mice

Charles Harvey Vannoy1, Victoria Leroy1, Qi Long Lu1

  • 1McColl-Lockwood Laboratory for Muscular Dystrophy Research, Carolinas Medical Center, Atrium Health, Charlotte, NC 28203, USA.

Molecular Therapy. Methods & Clinical Development
|November 13, 2018
PubMed

Insights

FKRP gene-replacement therapy shows promise for muscular dystrophy-dystroglycanopathies (MDDGs). This study in FKRP-mutant mice demonstrated dose-dependent restoration of biochemical defects and improved lifespan, supporting clinical trials.

Area of Science:

  • Genetics and Molecular Biology
  • Neurology
  • Regenerative Medicine

Background:

  • Muscular dystrophy-dystroglycanopathies (MDDGs) caused by FKRP gene mutations present a spectrum of severity with limited treatment options.
  • FKRP-related disorders lack a cure, necessitating exploration of novel therapeutic strategies for symptom management and disease modification.

Purpose of the Study:

  • To evaluate the safety and therapeutic potential of FKRP gene-replacement therapy using an AAV9 vector in a mouse model of FKRP-related MDDG.
  • To assess the longitudinal effects of dose-escalation gene therapy on biochemical, histopathological, functional, and lifespan outcomes.

Main Methods:

  • Systemic administration of AAV9-FKRP to FKRP P448L mice at 5 weeks of age.
  • Comprehensive analysis of protein/gene expression, histopathology, skeletal muscle, and cardiorespiratory function over 9 and 52 weeks.
  • Lifespan assessment in an advanced disease stage model.

Main Results:

  • FKRP gene-replacement therapy restored biochemical defects in a dose-dependent manner.
  • Treatment showed potential for improving disease progression trajectory and extending lifespan.
  • Histopathological and functional improvements were observed, supporting therapeutic efficacy.

Conclusions:

  • Early-stage FKRP gene-replacement therapy is safe and therapeutically beneficial in a mouse model of FKRP-related MDDG.
  • Dose-dependent restoration of FKRP function offers a promising avenue for treating these rare neuromuscular disorders.
  • These findings provide a strong rationale for initiating clinical trials in patients with FKRP-related disorders.
Keywords:
fukutin-related proteingene therapymuscular dystrophy-dystroglycanopathy

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