Poster 2: Cell and Tissue Studies
Small Activating Rna Therapy For Mucopolysaccharidosis Type I
Shaukat Khan
Nemours
BACKGROUND AND SIGNIFICANCE
Mucopolysaccharidosis type I (MPS I) is a rare disorder caused deficiency of the lysosomal enzyme ?-L-iduronidase (IDUA). MPS I leads to the accumulation of glycosaminoglycans (GAGs), heparan and dermatan sulfates, in the cells of various tissues, resulting in multi-system dysfunction, including CNS and musculoskeletal systems, which if untreated results in death in the first decade of life. Enzyme replacement therapy and hematopoietic stem cell transplantation are available. However, neither of the treatments completely restore CNS and skeletal system. We propose developing a small activating RNA (saRNA) therapeutic approach to test our hypothesis that targeted overexpression of gene products corrects abnormal systems biology and ameliorates brain and bone lesions. saRNA is chemically synthesized double-strand RNA oligonucleotides, which are highly selective and activate specific genes, leading to increased production of target proteins.
HYPOTHESIS
We will use gentamycin to read through stop codon mutations (W402X and Q70X) to restore low level (~3%) of IDUA activity followed by saRNA therapy that will boost the IDUA supraphysiological level and reduction in GAGs to normal level.
SIGNIFICANCE
There is no treatment for MPS I to completely restore CNS and bone lesions and removal of storage materials in the tissues. The current proposal with saRNA allows to activate the endogenous gene product of IDUA to deliver sufficient enzymes to hard-to-reach tissues; brain and bone.
Research Area: Skeletal Disorder & Treatments