Intraparenchymal or cisternal delivery of codon-optimized NAGLU expressing AAV8 capsid for disease correction in Mucopolysaccharidosis type IIIB mice.

Justin Dalugdug and Isabella Dinelli

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.

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2 Responses
  1. Jada Lewis

    Nice job. Can you comment on how faithful of a mouse model this is to the human condition (are all symptoms seen in humans shown as phenotypes in the mice and are there any phenotypes in mice that are not seen in humans)? Also, were there any phenotypes in the mice that were not corrected?

  2. Justin Dalugdug

    Thank you for your question, there are magnitudes of difference between mice models and humans. However, many studies including ours use mice models as they are an approximation of mammalian genetic and biological behavior. To this end, diseases and their symptoms are easily replicated in mice. There are of course limitations in defining behavioral change between children and mice. Those with MPSIIIB show decreased mentation and coordination. So our approximation for these behavioral changes were to measure the auditory thresholds of the mice.
    But other phenotypes carry over including, the fact that patients with MPSIIIB show hyperactivity. So, as children, they are hyperactive during the day. In mice, as they are nocturnal, proved to be hyperactive at night. This was measured using a running wheel apparatus connected to a sensor. However, this data showed too much variation to be significant, but the trend was there. In all, that being the only phenotype that was not significantly corrected.