Poster #70: NAGLU-M6P for the Potential Treatment of Sanfilippo B Syndrome
Title: Co-expression of S1S3 phosphotransferase in production cell line improves mannose 6-phosphorylation and cellular uptake of alpha-N-acetylglucosaminidase (Sanfilippo syndrome type B)
Date and Time: Monday, Feb. 7, 2022, from 3:00 – 5:00 PM PT (6:00 – 8:00 PM ET)
Session: Basic Science Abstracts
Presenter (In-person): Steven Le from Dr. Patricia Dickson’s lab, Division of Genetics and Genomic Medicine, Washington University of St. Louis
Sanfilippo B syndrome is characterized by a defect in the gene providing instructions for producing the enzyme alpha-N-acetylglucosaminidase (NAGLU), located in lysosomes, resulting in accumulation of glucosaminoglycans (GAGs).
NAGLU-M6P is an
enzyme replacement therapy approach utilizing co-expression of recombinant human NAGLU and S1S3, a modified GlcNAc-1-phosphotransferase, designed to increase M6P content and enhance subsequent cellular uptake of the enzyme. Binding experiments demonstrated superior binding up to 40% of NAGLU-M6P to the cation independent mannose 6-phosphate receptor (CI-MPR) compared to NAGLU produced without S1S3.
In Sanfilippo B patient fibroblasts, NAGLU-M6P exhibited robust M6P-dependent uptake into cells and reduction of intracellular heparan sulfate.
In vivo experiments in a Sanfilippo B mouse model showed broader distribution of NAGLU enzyme activity in mice that received NAGLU-M6P versus NAGLU.
“These data show the potential utility of recombinant NAGLU and S1S3 co-expression as an effective
enzyme replacement therapy in Sanfilippo B syndrome,” said Dr. Lin Liu, Vice President, Research & Development at M6PT. “We look forward to continued development of this promising therapeutic approach and hope to validate these preclinical results in patients with Sanfilippo B syndrome.”
Poster #120: S1S3
Gene Therapy for the Potential Treatment of Lysosomal Disorders
Title: A novel S1S3 phosphotransferase co-expression gene therapy platform for lysosomal disorders
Date and Time:
Contemporary Forum Talk (including live moderated Q&A): Thursday, Feb. 10, 2022, from 10:30 – 11:30 AM PT (1:30 – 2:30 PM ET) followed by:
Poster Session: Thursday, Feb. 10, 2022, from 3:00 – 5:00 PM PT (6:00 – 8:00 PM ET)
Session: Contemporary Forum Poster Presentations
Presenter (In-person): Dr.
Andrew Hedman, M6PT Scientist
LSDs are rare, genetic, life-threatening diseases marked by defects in specific
lysosomal enzymes.
M6PT has developed a
gene therapy platform utilizing adeno-associated virus-9 (AAV9) vector to deliver S1S3 phosphotransferase (PTase) and recombinant
lysosomal enzymes in LSDs. This co-expression
gene therapy is designed to enhance M6P content on the enzyme, allowing for correct targeting to the lysosome.
Investigators reported the potential utility of this
gene therapy platform using various LSD models. In a mouse model of Mucolipidosis type II, an LSD with GlcNAc-1-phosphotransferase deficiency, AAV9 expression of S1S3 PTase restored phosphorylation of
lysosomal enzymes. In addition, M6P content was increased in mouse tissues treated with AAV9 vectors co-expressing S1S3 PTase and α-Gal A, an enzyme involved in
Fabry disease, as compared to treatment with an AAV9 vector expressing α-Gal A alone.
“We are encouraged by the positive preclinical results from our
gene therapy co-expression studies,” said Dr. Hedman. “We believe that an S1S3-based
gene therapy platform can improve lysosomal enzyme cross-correction in a variety of LSDs and represents a potential advancement in the treatment of these disorders.”
Poster #105: M011 for the Potential Treatment of
Gaucher Disease
Title: M011: A novel highly phosphorylated β-glucocerebrosidase enzyme with broader tissue biodistribution for the treatment of Gaucher disease
Date and Time:
Contemporary Forum Talk: Thursday, Feb. 10, 2022, from 1:00 – 2:00 PM PT (4:00 – 5:00 PM ET) followed by:
Poster Session: Thursday, Feb. 10, 2022, from 3:00 – 5:00 PM PT (6:00 – 8:00 PM ET)
Session: Contemporary Forum Poster Presentations
Presenter (Virtual): Russell Gotschall, Vice President, Research & Development, M6PT
Gaucher disease is a rare, autosomal recessive metabolic disorder in which deficiency of the enzyme β-glucosidase results in harmful accumulation of glucosylceramide in tissue macrophages and other cells.
M011 is a novel recombinant human β-glucosidase (rhGCase) enzyme co-expressed with S1S3 PTase that produces rhGCase with a high M6P levels, resulting in high levels of bis-phosphorylated glycans and high binding affinity for the CI-MPR.
In vivo experiments in a Gaucher mouse model showed that M011 reduced glucosylshpingosine from the liver and spleen and cleared bone and skeletal muscle substrate more effectively than imiglucerase, the enzyme currently used for
enzyme replacement therapy in
Gaucher disease. In addition, M011 showed more efficient cellular uptake and broad distribution in tissues.
“The superior efficacy and broad distribution of M011 demonstrate its potential as a viable treatment approach for
Gaucher disease, including in types affecting the central nervous system,” said Mr. Gotschall. “We are encouraged by these highly promising results and look forward to continued development of M011.”
Poster #106: M021 for the Potential Treatment of
Pompe Disease
Title: M021: A uniquely glycosylated, highly phosphorylated acid-alpha glucosidase enzyme replacement therapy for the treatment of Pompe disease
Date and Time: Thursday, Feb. 10, 2022, from 3:00 – 5:00 PM PT (6:00 – 8:00 PM ET)
Session: Contemporary Forum Poster Presentations
Presenter (Virtual): Russell Gotschall, Vice President, Research & Development, M6PT
Pompe disease is a rare, inherited metabolic disorder in which deficiency of the enzyme α-glucosidase (GAA) results in defective lysosomal glycogen catabolism.
M021 is a novel recombinant human GAA (rhGAA) enzyme co-expressed with S1S3 PTase that enhances M6P levels, resulting in high levels of bis-phosphorylated glycans, high affinity for the CI-MPR, and low levels of neutral oligosaccharides.
In vivo experiments in GAA deficient mice showed that M021 significantly reduced glycogen accumulated in muscles compared to alglucosidase alfa, the current
enzyme replacement therapy for
Pompe disease.
“These data demonstrate the continued development potential of M021 as a next-generation treatment for
Pompe disease,” said Mr. Gotschall. “We plan to complete efficacy evaluations of M021 in mice and hope to advance this potential therapeutic approach to future clinical studies.”
For more information, registration details and to access the live streamed events, presentations, and Q&A sessions, please go to
WORLDSymposium™. The abstracts will also be made available on the
Publications section of M6PT’s
corporate website following the presentations.
