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Correction of Disease Phenotype in Pompe Disease Knockout Mice Following Cationic Lipid-GL-67-Mediated Gene Therapy
Frank Martiniuk1,2, Justin Martiniuk1,2, Adra Mack1,2
1JME Group Associates, Inc, Roseland, New Jersey, USA.
Insights
Gene therapy using a cationic lipid delivery system successfully restored lysosomal acid α-glucosidase (GAA) activity in Pompe disease models. This approach reversed muscle weakness and extended lifespan, offering a promising treatment for Pompe disease.
Area of Science:
- Biochemistry
- Genetics
- Molecular Biology
Background:
- Pompe disease (PD) is a genetic disorder caused by a deficiency in lysosomal acid α-glucosidase (GAA).
- Infantile PD presents with severe symptoms within the first year, while adult-onset forms primarily affect skeletal muscles.
- Efficient gene therapy for muscle-affecting diseases like PD is challenging due to organ size and transfection difficulties.
Purpose of the Study:
- To evaluate a cationic lipid-based gene delivery system for Pompe disease therapy.
- To assess the efficacy of a plasmid vector carrying human GAA cDNA complexed with GL-67 lipid.
Main Methods:
- Transient transfection of human PD fibroblast cell lines with the GAA expression plasmid and GL-67 lipid.
- Treatment of GAA knockout mice with the plasmid-lipid complex via intraperitoneal injection.
- Analysis of GAA activity in various tissues and assessment of clinical phenotypes and lifespan.
Main Results:
- Maximal human GAA activity was achieved in transfected cells using 20 nmol of GL-67 lipid.
- GAA knockout mice showed substantial increases in GAA activity in heart, diaphragm, and skeletal muscle.
- Muscle weakness was reversed, and lifespan was extended to near-normal levels in treated mice.
Conclusions:
- Cationic lipid-mediated gene delivery of human GAA cDNA shows potential as an effective treatment for Pompe disease.
- This gene therapy approach offers a promising strategy for addressing the underlying genetic defect in PD.
Background:
Genetic deficiency of lysosomal acid α-glucosidase or acid maltase (GAA) results in Pompe disease (PD) or glycogen storage disease type II, encompassing subtypes of varying severity. The infantile form presents as hypotonia, muscle weakness, and congestive heart failure in the first year, while the adult onset forms are limited to skeletal muscle. Gene therapy for diseases that affect muscles or organs (as PD) may be very difficult due to their size or location and our ability to transfect these organs with high efficiency.
Methods:
We evaluated a plasmid vector carrying the cytomegalovirus promoter linked to the human GAA cDNA complexed with the cationic lipid GL-67 as a delivery system for therapy of PD.
Results:
A human PD fibroblast cell line was transiently transfected with increasing amounts of the cationic lipid GL-67 complexed to the human GAA expression plasmid. Cells showed a significant increase in human GAA activity with 20 nmol of the cationic lipid, resulting in maximal expression. GAA knockout mice were treated intraperitoneally every 2 weeks for four months with 100 µg of plasmid and 2 mM GL-67 lipid. Tissues, including heart, diaphragm, and skeletal muscle showed substantial increase in GAA activity. More important, the clinical phenotype of hind and forelimb muscle weakness was reversed and life span extended to almost normal longevity.
Conclusions:
These data suggest that cationic lipid mediated gene delivery of the human GAA cDNA may be an effective treatment for PD.
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