Gene Therapy Shows Promise for Long-Term Correction of Pompe Disease in Mice
A single dose of a novel gene therapy has demonstrated the potential for long-term correction of Pompe disease in a mouse model, normalizing muscle function for over a year. The therapy utilizes genetically engineered sequences designed to significantly boost enzyme production specifically within muscle cells, achieving protein levels up to 30 times higher than those seen with previous approaches.
The research, published in Human Gene Therapy, details a new strategy for delivering a functional copy of the GAA gene – the gene defective in Pompe disease – directly to muscle tissue. This approach aims to overcome the limitations of current treatments, which often require frequent enzyme infusions and can be hampered by the development of antibodies.
Understanding Pompe Disease
Pompe disease is a rare, inherited metabolic disorder caused by mutations in the GAA gene. This gene provides instructions for making acid alpha-glucosidase (GAA), an enzyme crucial for breaking down glycogen, a complex sugar molecule stored in cells for energy. When GAA is deficient or non-functional, glycogen accumulates to toxic levels, particularly in muscle cells, leading to progressive muscle weakness and organ damage.
Symptoms of Pompe disease can vary depending on the age of onset. In infants, the disease typically presents with severe muscle weakness, heart problems, and respiratory difficulties. Later-onset forms can manifest as progressive muscle weakness in the limbs and trunk, often leading to mobility issues and respiratory compromise.
The Challenge of Gene Therapy for Muscle Diseases
Gene therapy offers a potential one-time treatment for Pompe disease by delivering a healthy copy of the GAA gene to muscle cells, enabling them to produce functional enzyme. Adeno-associated viruses (AAVs) are commonly used as vectors for this purpose due to their ability to efficiently deliver genetic material without causing illness. However, simply getting the gene into muscle cells isn’t enough. The gene must be effectively “turned on” – a process known as gene expression – to produce sufficient levels of the GAA enzyme.
Traditionally, researchers have relied on genetic sequences called promoters to drive gene expression. Promoters act as switches, controlling when and where a gene is activated. However, achieving high levels of sustained gene expression in muscle tissue has proven challenging.
Supercharging Gene Expression with Cis-Regulatory Elements
The researchers in this study took a novel approach, employing data-mining techniques to identify a set of highly effective promoters, termed cis-regulatory elements (CREs), specifically designed to enhance gene expression in muscle cells. These CREs were then incorporated into the AAV-based gene therapy vector, positioned upstream of the GAA gene.
In laboratory studies, AAV vectors utilizing these CRE promoters demonstrated a remarkable increase in gene expression. When used with a luciferase reporter gene – a gene that produces a measurable bioluminescent signal – the CRE-enhanced vectors achieved up to 30 times higher protein expression in muscle cells compared to vectors using standard promoters.
Restoring Muscle Function in a Mouse Model
To assess the therapeutic potential of this approach, the researchers tested the gene therapy in a mouse model of Pompe disease. The results were encouraging. Treatment with the CRE-enhanced AAV vector led to a significant reduction in glycogen accumulation in skeletal muscles, diaphragm, and heart. More importantly, the therapy resulted in long-term normalization of muscle function, with treated mice exhibiting grip and hanging strength comparable to that of healthy mice. These improvements were sustained for over a year following a single dose of the gene therapy.
The study authors concluded that the use of CREs “resulted in relatively robust expression in the skeletal muscle, diaphragm, and heart, leading to phenotypic correction of these affected tissues in the treated [Pompe] mice.”
Limitations and Future Directions
While these findings are promising, the researchers acknowledge certain limitations. Notably, the current gene therapy approach does not address the manifestations of Pompe disease in the brain and spinal cord. The researchers suggest that developing AAV vectors capable of efficiently delivering the therapeutic gene to these tissues is crucial for a comprehensive treatment strategy.
“Ideally, novel AAV capsids [outer shells] that enable efficient targeted transduction [delivery of genetic material to cells] of skeletal muscle, diaphragm, heart and brain would be necessary to effectively treat all clinical manifestations of Pompe disease,” they wrote.
Despite these limitations, the study provides strong support for the use of CRE arrays to enhance the performance of gene therapy vectors for Pompe disease. The researchers believe these findings justify the initiation of new clinical trials to evaluate the safety and efficacy of this approach in human patients. The team concluded that the preclinical study “strongly supports the use of CRE arrays to enhance the performance of gene therapy vectors for treating Pompe patients, justifying new gene therapy clinical trials.”
