Pramod Mistry, MBBS, PhD, MA, MD

We have focused on deep clinical phenotyping of patients as the foundation of genomic, biomarker and modifier gene studies in Gaucher disease. This approach has also allowed forumating key research questions tgo the lab and out extensive collection of mouse models. In this way, our program represents iterative bedside to bench and back to bench research program that makes incremental improvement in patient care and outcomes. We collaborate with international colleagues to decipher global patterns of disease, genotypes, phenotypes and natural history. Our in- house Registry and International Collaborative Gaucher Registry has propelled and validated numerous basic mechanistic findings derived from our lab studies using cells and mouse models. In the clinic, we are a site for clinical trials of recombinant enzyme replacement therapy and small molecule therapy. Pre-clinical studies on gene editing therapy are in progress.

Gaucher disease shows extraordinary phenotypic varaiabilty even among affected sib-pairs and among patients with identical genotypes. We are examining several candidate genes in glycosphingolipid metabolic pathways and in pro-inflammatory pathways as potential modifier genes. We are also applying several genomic approaches (WES, WGS, scRNAseq snRNAseq) for identification of modifier genes. Discovery of modifier genes will impact on patient management through more accurate prediction of prognosis and enable pre-emptive therapy of those at highest risk.

Rare Gaucher disease is also illuminating common diseases such as B cell malignancies, hepatocellular carcinoma and Parkinson disease. Patient with Gaucher disease are at high risk of these complications and interestingly even heterozygote carriers of GBA mutations are at increased risk of Parkinson disease. We are actively studying these links and researching into underlying mechanisms.

Our clinical translational model developed for Gaucher disease is applicable for a range of inborn errors of metabolism affecting the liver such as Glycogen Storage disease type 1a, porphyrias, Wilson disease, alpha 1 antitrypsin deficiency and hemochromatosis.