Pompe Disease Drug Discovery Service

Creative Biolabs develops and delivers one-stop research solutions. Our core is to work with our partners to solve complex therapeutic challenges. When partnering with us there is no need to change providers, which can be both time-consuming and expensive. We are flexible to meet the unique needs of client projects.

Overview of Pompe Disease (PD)

PD is a rare autosomal recessive disorder caused by mutations in the GAA gene, located on chromosome 17, which encodes acid α-1, 4-glucosidase (GAA). The resulting glycogen accumulation causes cellular dysfunction and progressive damage to skeletal, respiratory, and cardiac muscles. Currently, enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA) is the only specific treatment for PD.

Fig.1 Schematic representation of GAA alteration that caused glycogen storage in lysosomes of PD cells. (Taverna, 2020)

Creative Biolabs' Pathogenesis Research of PD

Our understanding of the mechanisms driving the pathogenesis of muscle damage in PD is rapidly evolving. Pathogenesis is believed to be a staged process involving the gradual accumulation of glycogen in the lysosomal lumen, the rupture of the lysosomal membrane due to mechanical pressure, the entry of glycogen, and potentially toxic substances into the cytoplasm, and the eventual destruction of muscle structures.

Fig.2 Pathogenic cascade of muscle damage in PD. (Meena, 2020)

Creative Biolabs' Animal Models for PD

To design and evaluate new therapeutic strategies, the availability of animal models that mimic human diseases is essential. Five mouse models have been developed to evaluate Pompe treatment strategies in an in vivo environment by targeting the disruption of the GAA gene. The first knockout mouse model was generated by targeted disruption of exon 13. The second knockout mouse model was generated in which exon 6 of the GAA gene was replaced by a cassette containing a neomycin resistance gene into exon 6 flanked by LoxP sites (6^neo/6^neo). This model has features of both the adult and infantile phenotypes of Pompe disease. A third mutant mouse model was created by mating 6^neo/6^neo mice to Cre-producing mice. Two additional models were developed because successive GAA administration resulted in an immune response in mice with the above immune capacity. The exon 6 KO mouse model, therefore, was further improved. The fifth animal model (GAA KO/SCID mice) was developed to avoid the production of anti-hGAA antibodies after enzyme administration.

Therapies for PD

• ERT

The discovery of a mannose-6-phosphate (M6P) receptor-mediated lysosomal uptake pathway can lead to cross-correction, indicating the possibility of lysosomal supplementation in extracellular media. Currently, the only clinically available treatment for PD is ERT. In general, the goal of ERT in lysosomal storage diseases is to compensate for the mutant enzyme through the continuous supply of functional enzymes.

• Gene Therapy

Since PD is a monogenic disorder, it is an ideal target for gene replacement strategies. In vivo gene therapy involves injecting gene vectors (viral or non-viral) directly into the patient's cells. Gene therapy is currently being developed to treat genetic diseases. Gene therapy aims to provide a continuous internal source of enzymes. Liposomes are the most promising delivery systems for genes and they are among the most studied non-viral vectors because of their similarity to cell membranes.

Creative Biolabs' One-stop Shop Services for PD Preclinical Drug Discovery

• In Vitro Services
• In Vivo Services
• Ex Vivo Services
• Discovery Services
• Development Services

Creative Biolabs' team of highly qualified and experienced technical staff will work with you to develop and deliver testing and analytical solutions to add value to your product or project. We have the expertise to optimize each stage of disease research. If you are interested in our services, please feel free to contact us to advance your PD projects.

References

1. Taverna, S.; et al. Pompe disease: pathogenesis, molecular genetics and diagnosis. Aging. 2020, 12(15): 15856.
2. Meena, N.K.; Raben, N. Pompe disease: new developments in an old lysosomal storage disorder. Biomolecules. 2020, 10(9): 1339.