Authors: Kimberly Hawkins, Elizabeth Butterworth Hosaka, Courtney Rouse, Mi-Jung Kim, Isabella Dinelli, Aishwarya Kunta, Erinn Rosenkrantz, Nadia Kabbej, Justin Dalugdug, Darin J. Falk, Coy D. Heldermon
Faculty Mentor: Dr. Coy D. Heldermon
College: College of Medicine
Mucopolysaccharidoses IIIB (MPSIIIB) is a genetic lysosomal storage disease caused by mutations in N-acetyl-glucosaminidase (NAGLU), resulting in abnormal functioning of lysosomes and progressive central nervous system (CNS) deterioration. We demonstrated AAV8 viral delivery provides a broader conversion of NAGLU protein activity in the MPS IIIB mouse brain compared to other viral transportation versions. Hypothesis: The tcmAAV8 delivery method carrying a codon-optimized NAGLU (coNAGLU) will improve disease outcomes in the MPS IIIB mouse model. Methods: Affected mice received two sets of injections of AAVtcm8 containing NAGLU, known as an intracranial six site (IC6) and cisterna magna (ICM) injections into the brain. Normal, heterozygous, and affected mice were observed for survival, behavioral, and hearing assessments and biochemical study of diseased tissue. Results: IC6 or ICM AAV8-mediated administration resulted in increased NAGLU protein activity in the forebrain, hindbrain, cerebellum, spinal cord, and reduced signs of disease. A significant reduction in lysosomal distention is revealed animals receiving IC6 or ICM when compared to affected mice. Significant improvement of hearing loss was observed as measured by auditory brainstem response (ABR). Extension of median lifespan was observed in IC6 and ICM treated animals compared to normal-type mice from on average 322 days to 537 days.