Algorithm for the early diagnosis and treatment of patients with cross reactive immunologic material-negative classic infantile pompe disease: a step towards improving the efficacy of ERT.

1)Development of new non-invasive laboratory diagnostic methods using enzymology and molecular diagnostic techniques for Glycogen Storage Diseases (GSDs) and Lysosomal Storage Diseases (LSDs) like Pompe, Fabry, Gaucher, MPS - for early diagnosis and treatment modalities. Exploration of new high throughput diagnostic platforms with an idea of implementation into New born screening (NBS)of these diseases.

2)Clinical research studies associated with Pompe disease with a goal to improve the diagnosis, current therapies and patient care, with special emphasis on clinical development of Cross Reactive Immunologic Material (CRIM) diagnostic methods and association with underlying pathogenic GAA mutations and clinical correlations.

3) Clinical research studies involving other common LSDs (Fabry, MPSI,II,IVa and VI, Gaucher, Wolman disease and more) focusing on early diagnosis and new born screening.

4)Understanding the hepatocellular adenoma (HCA) and hepatocellular carcinomas (HCC) transformation in GSD I, using paired samples from resected adenomas and adjoining liver tissue. Experiments use SNP and expression microarray analysis, miRNA and CNV analysis in collaboration with other investigators.

5)Pursuing genotype-phenotype correlations for various clinical phenotypes of GSD IX, in order to better understand clinical heterogeneity. Severe phenotypes of GSD IX resulting in liver cirrhosis and Cardiac involvement are of special interest to us, especially their association with the underlying pathogenic mutations.

6)Research on Pompe/Mannose-6-phosphate receptor (M6PR300) double knock out mice to understand the role of M6PR in rhGAA uptake and glycogen clearance and also beta-agonist like Clenbuterol.

RESEARCH INTERESTS

A multidisciplinary approach to care of individuals with genetic disorders in conjunction with clinical and bench research that contributes to:
1) An understanding of the natural history and delineation of long term complications of genetic disorders  with a special focus on liver Glycogen storage disorders, lysosomal disorders with a special focus on Pompe disease, Down syndrome and hypophosphatasia
2) ) The development of new therapies such as AAV gene therapy, enzyme therapy, small molecule and other approaches for genetic disorders through translational research

3) The development and execution of large multicenter trials to confirm safety and efficacy of potential therapies
4) Role of antibodies/immune response in patients on therapeutic proteins and AAV gene therapy

. Glycogen Storage Disease (GSD): We are actively following subjects with all types of Glycogen Storage Disease, with particular emphasis on types I, II, III, IV, VI and IX. The goal of the treatment team is to better determine the clinical phenotype and long term complications of these diseases. Attention to disease manifestations observed in adulthood, such as adenomas and risk for HCC, is of paramount importance in monitoring and treating these chronic illnesses. We are establishing clinical algorithms for managing adenomas, and the overall management of these patients including cardiac, bone, muscle and liver issues. A special focus is biomarker discovery, an Omics approach including metabolomics and immune phenotyping. We are working on AAV gene therapy for several hepatic GSDs

.Lysosomal Storage Disease: The Duke Lysosomal Storage Disease (LSD) treatment center follows and treats patients with Pompe, Gaucher, Fabry, Mucopolysaccharidosis, Niemann Pick, LAL-D and other LSD's. The Duke Metabolism Clinical Research Team is exploring many aspects of enzyme replacement therapy (ERT), including impact on different systems, differential response, and long term effects. Other symptomatic and treatment interventions for this category of diseases are also being explored in the context of clinical care.

. Pompe Disease: The care team has extensive experience in the care of infants and adults with Pompe disease and was instrumental in conducting clinical trials and the bench to bedside work that led to the 2006 FDA approval of alglucosidase alfa, the first treatment for this devastating disease. We are currently focusing on role of antibodies/immune response on patient outcome and role of immune modulation/immune suppression as an adjunct to ERT. Our team is also working on AAV gene therapy for Pompe disease. A focus is on newborn screening (NBS) and understanding the clinical phenotype and management approaches for babies identified via NBS

.  Hypophosphatasia: We follow a large cohort of patients with HPP. The goal is to understand the features of the disease beyond bone disease, development of biomarkers, role of ERT and immune responses in HPP

. Neuromuscular disorders: We are collaborating with neurologists, cardiologists and neuromuscular physicians to serve as a treatment site for clinical trials in these diseases. We are currently involved in trials of DMD and are working closely on setting up collaborations for studies in SMA.