Research /

The Yash Gandhi Foundation has awarded a total of $164,000 in research grants to the following researches and institutions listed below.


Funding from the Yash Gandhi Foundation has given my laboratory a valuable opportunity to initiate new research on mucolipidosis II (I-cell disease) in hopes of finding treatments for this devastating lysosomal disorder. - Dr. Richard Steet, UGA - Complex Carbohydrate Research Center

The University of Georgia Complex Carbohydrate Research Center and the University of Washington.

Grant Amount: $60,000

Grant Date: March 2016

Research Proposal: The current proposal will continue to investigate the molecular basis of ML disease and address the question of how GlcNAc-1-phosphotransferase recognizes 60 different lysosomal acid hydrolases while avoiding acting on the many other glycoproteins synthesized by the cell. This information may point to new ways to treat ML disease that are tailored for specific tissues.

Status: Research ongoing

The University of Georgia Complex Carbohydrate Research Center and the University of Washington.

Grant Amount: $48,000

Grant Date: February 2015

Research Proposal: This new research grant will allow these organizations to focus on increasing the understanding of how ML2-associated mutations impact the function of the GlcNAc-1-phosphotransferase enzyme, a key enzyme involved in ML-2. The proposed studies will also provide new insight into the poorly understood role of the gamma subunit of the GlcNAc-1-phosphotransferase enzyme and how mutations in this subunit cause disease.

Status: Research ongoing

Dr. Stuart Kornfeld at Washington University School of Medicine, St. Louis, MO.

stuart
About Dr. Kornfeld: Dr.Stuart Kornfeld,MD, is a Professor of Medicine at Washington University in St. Louis. In the early 1980s he discovered the mechanism whereby the Mannose 6-phosphate recognition marker is added to newly synthesized lysosomal acid hydrolases and showed that mutations in the enzyme that mediates the first step in this pathway are the cause of Mucolipidosis II/III. Since then he has studied many aspects of the Mannose 6-phosphate trafficking pathway. He is a member of the National Academy of Sciences and has received many awards for his research contributions.

Grant Amount: $18,000

Grant Date: July 2013

Research Proposal: Evaluate mutations in the GNPTAB gene that give rise to mucolipidosis II (I-­‐cell disease) and mucolipidosis IIIα/β(Pseudo-­‐Hurler Polydystrophy). There are 2 specific aims of this project; (1) Attempt to rescue the misfolding of the 9 mutant enzymes using pharmacological agents; (2) Define the basis for the lack of activity toward lysosomal acid hydrolases in the mutants that fold properly and localize correctly in the Golgi.

Status: Research completed. Please see below for results.

Result: Drs. Steet and Kornfeld have provided a midterm update on their YGF-funded research project. They are pleased to report the identification of a new region within the GlcNAc-1-phosphotransferase enzyme that is responsible for the specific recognition of lysosomal enzymes. This finding is significant since it helps explain why certain ML mutations contribute to ML-II vs ML-III, and deepens our understanding of the genetic basis for this disease. The researchers hope to utilize this information to develop therapies for ML disease that can be tailored to specific mutations found in patients.

Dr. Richard Steet at The University of Georgia, Complex Carbohydrate Research Center, Athens, GA.

richard
About Dr. Steet: Dr. Richard Steet, Ph.D. is an Associate Professor of Biochemistry and Molecular Biology and a member of the Complex Carbohydrate Research Center at the University of Georgia. His laboratory primarily studies the pathogenesis of lysosomal diseases such ML-II using zebrafish models. Dr. Steet maintains an active collaboration with Dr. Kornfeld to study aspects of the mannose 6-phosphate trafficking pathway using the zebrafish system.

Grant Amount: $18,000

Grant Date: July 2013

Research Proposal: Evaluate mutations in the GNPTAB gene that give rise to mucolipidosis II (I-­‐cell disease) and mucolipidosis IIIα/β (Pseudo-­‐Hurler Polydystrophy). There are 2 specific aims of this project; (1) Attempt to rescue the misfolding of the 9 mutant enzymes using pharmacological agents; (2) Define the basis for the lack of activity toward lysosomal acid hydrolases in the mutants that fold properly and localize correctly in the Golgi (joint collaboration on this project between Drs. Steet and Kornfeld).

Status: Research completed. Please see below for results.

Result: Drs. Steet and Kornfeld have provided a midterm update on their YGF-funded research project. They are pleased to report the identification of a new region within the GlcNAc-1-phosphotransferase enzyme that is responsible for the specific recognition of lysosomal enzymes. This finding is significant since it helps explain why certain ML mutations contribute to ML-II vs ML-III, and deepens our understanding of the genetic basis for this disease. The researchers hope to utilize this information to develop therapies for ML disease that can be tailored to specific mutations found in patients.

Dr. Sara Cathey at Greenwood Genetic Center, Greenwood, SC.

sara
About Dr. Cathey: Dr. Cathey is a clinical geneticist certified by both the American Board of Medical Genetics (2007) and the American Board of Pediatrics (2000) and is a fellow of the American College of Medical Genetics and the American Academy of Pediatrics.Her special areas of interest include birth defects, intellectual disabilities, and lysosomal diseases. Dr. Cathey has numerous publications in lysosomal storage disorders.

Grant Amount: $20,000

Grant Date: Jan 2012

Research Proposal: To determine the effectiveness of the compound PTC124 (Ataluren) in reading through nonsense mutations in mucolipidosis II (MLII).

Status: Research completed. Please see below for results.

Result: PTC124 is a compound that promotes the "read-through" of DNA nonsense mutations by inserting a random amino acid in place of the premature termination codon, allowing translation to continue until the proper termination codon is reached. Our aim was to treat the fibroblasts of patients with mucolipidosis type II with PTC124 and then measure the activities of several lysosomal enzymes inside the cells as an indirect measurement of GlcNAc-1-phosphotransferase activity. A modest but statistically significant increase in both alpha-fucosidase and beta-glucuronidase activity was observed in cells treated with 20 μM PTC124 compared to untreated cells. However, the results obtained in the first set of experiments were not reproducible, and PTC124 does not appear to have a significant positive effect on lysosomal enzyme activity in fibroblasts harboring a nonsense mutation.