Advance-CTR

Advance-CTR Pilot Projects Program (2018)

"Identification of Gene Pathway Involved in Phenotype Modification of Pompe Disease"

Co-PI: Ece Uzun, PhD

Pompe disease is an autosomal recessive condition caused by deficiency of lysosomal enzyme acid alpha glucosidase (also known as acid maltase). Patients with Pompe disease may present in infancy, childhood or adulthood with cardiac and/or skeletal muscle involvement resulting from the lysosomal accumulation of glycogen. Current therapy includes enzyme replacement therapy (ERT) with synthetic enzyme alglucosidase alfa. The age of onset, extent of organ involvement, degree of disease severity and response to ERT with alglucosidase alfa show marked variability between patients. While some genotype-phenotype correlations have been observed, substantial variability has been documented between patients with the same genotype in the GAA gene that encode acid alpha glucosidase. Additionally, a subset of patients with Pompe disease develop high titer antibodies against alglucosidase alfa, significantly compromising the effect of ERT and show clinical decline. Patients who are negative for Cross-Reactive Immunologic Material (CRIM) are predicted to show pronounced immunologic response. These patients usually have null or truncating GAA mutations. However, a subset of CRIM-positive patients develops high titer antibodies. These observations suggest the presence of genetic or non-genetic modifying factors, which may contribute to the variability of phenotype and ERT response among patients with Pompe disease. Potential phenotype-modifying pathways include tissue-specific factors that control aberrant splicing or enzyme activity, post-translational processing of residual enzyme, metabolism of the enzyme, and sensitivity to tissue damage such as inflammatory response. This study aims to identify potential pathway/gene sets that modify the phenotype and/or pronounced anti-ERT immune response in patients with Pompe disease. Our collaborator Dr. Kishnani at Duke University and the PI have previously sequenced the whole exome (WES) on blood or fibroblast specimens from 96 patients with Pompe disease, who were very carefully phenotyped. The WES data and phenotype data is stored in a de-identified form. Dr. Padbury and colleagues have successfully applied pathway/gene set approaches to identify pathways potentially associated with preeclampsia and preterm birth. We will apply pathway analysis approaches to the Pompe WES data. Comprehensive understanding of the disease process and therapeutic responses in Pompe disease would guide research and therapeutic approaches other lysosomal storage diseases. Network analysis approach applied here is generalizable to other conditions and not limited to rare genetic conditions.

Mentor

Jim Padbury, MD