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Lentiviral Hematopoietic Stem Cell Gene Therapy Corrects Murine Pompe Disease

Merel Stok1,2,3, Helen de Boer1,4, Marshall W Huston1,5

  • 1Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Molecular Therapy. Methods & Clinical Development
|May 29, 2020
PubMed

Insights

Pompe disease gene therapy using a codon-optimized GAA gene in hematopoietic stem cells normalized motor function and reduced glycogen buildup in the brain, heart, and muscles of mice.

Area of Science:

  • Biochemistry
  • Genetics
  • Neuroscience

Background:

  • Pompe disease is a genetic disorder causing progressive muscle weakness due to mutations in the acid α-glucosidase (GAA) gene.
  • Current enzyme replacement therapy (ERT) has limitations, including immune responses and inability to cross the blood-brain barrier, leading to high infant mortality.
  • Previous studies showed partial correction with ex vivo hematopoietic stem cell gene therapy.

Purpose of the Study:

  • To evaluate the efficacy of ex vivo hematopoietic stem cell gene therapy using a codon-optimized GAA gene (GAAco) in a mouse model of Pompe disease.
  • To assess the correction of glycogen storage and motor function in multiple tissues, including the brain.
  • To analyze lentiviral vector integration sites for safety.

Main Methods:

  • Hematopoietic stem cells were genetically modified with a codon-optimized GAA gene (GAAco) using a lentiviral vector.
  • Mice with Pompe disease were treated with the gene-modified stem cells.
  • Glycogen levels in heart, muscles, and brain were measured.
  • Motor function was assessed.
  • Brain tissue was analyzed for GAA enzyme expression in microglia and astrocytes.
  • Lentiviral vector insertion sites were analyzed.

Main Results:

  • Gene therapy with GAAco led to near-normalization of glycogen levels in the heart, muscles, and brain.
  • Complete normalization of motor function was achieved in treated mice.
  • GAA enzyme expression was detected in a significant proportion of brain microglia and all astrocytes.
  • Vector insertion site analysis showed no preference for integration near proto-oncogenes, indicating a favorable safety profile.

Conclusions:

  • Ex vivo hematopoietic stem cell gene therapy with GAAco offers a promising therapeutic strategy for Pompe disease.
  • This approach effectively corrects glycogen storage and restores motor function, even addressing brain involvement.
  • The findings support further development of this gene therapy for treating human Pompe disease.

Keywords:
acid α-glucosidasecentral nervous systemhematopoietic stem cell transplantationlentiviral vectormurine Pompe diseaseskeletal muscle

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