Dr. Lin Liu, M6P Therapeutics’ Senior Scientist & Director of R&D, presented recent findings during a poster session at the WORLDSymposium 2020.
Lysosomal storage diseases (LSDs) comprise ~50 inherited disorders characterized by the accumulation of un-degraded macromolecules due to a deficiency of particular acid hydrolases. The current treatment for LSDs is enzyme replacement therapy (ERT). Beyond ERT, gene therapy has been proposed to be a long-term cure.
A limitation for existing ERT and gene therapy approaches is the inability to produce enzyme containing high levels of mannose 6-phosphate (M6P) required to mediate binding to cell surface M6P receptors and subsequent delivery to lysosomes. However, recent advances with an engineered truncated GlcNAc-1-phosphotransferase (S1-S3 Ptase) demonstrated that phosphorylation of expressed lysosomal enzymes can be greatly increased by co-transfection (Molecular Therapy: Methods & Clinical Development 5, 59-65 (2017)).
Using the S1-S3 Ptase, we have developed a bicistronic expression platform to express a lysosomal enzyme and S1-S3 Ptase in one vector.
Six different enzymes produced using our bicistronic platform exhibited enhanced binding to M6P receptors compared to the wildtype enzyme that is dependent on endogenous GlcNAc-1-phosphotransferase. Furthermore, enzymes produced with our bicistronic platform were taken up much more efficiently than wildtype in cell uptake experiments using patient or enzyme deficient fibroblast. In addition, the S1-S3 Ptase itself is able to be incorporated into AAV for the gene therapy of Mucolipidosis.
In conclusion, we believe that our new bicistronic expression platform has the potential to create superior enzyme replacement and gene therapies compared to other methods that do not have high M6P levels to facilitate enhanced delivery of therapeutic enzymes to the lysosomes of many tissues within the body.
Please contact Dr. Liu using our Contact Form.