There is currently no treatment for the devastating impacts of neurodegeneration associated with the lysosomal storage disease, mucopolysaccharidosis IIIA (MPS IIIA) (Sanfilippo A). Children inheriting this monogenetic disorder are typically asymptomatic at birth, but at age 1-4 begin to develop severe behavioral problems including aggression and sleep disturbances, and cognitive deterioration that progresses to dementia. Patients usually survive to early adulthood and require intense supportive care. Gene therapy can effectively treat the root cause of the disease, a deficiency in the gene encoding N-sulfoglucosamine sulfohydrolase (SGSH), and correct the pathology at the cellular level, leading to clearance of accumulated glycosaminoglycans (GAGs) in lysosomes. Because the neuropathology of MPS IIIA is global, affecting all areas of the brain, effective gene delivery to the central nervous system (CNS) is the greatest obstacle to treatment for this, and many other lysosomal storage diseases. The immediate goal of this project is to develop a gene therapy procedure to treat MPS IIIA disease. It has been observed recently that recombinant adeno-associated virus (rAAV) vectors derived from serotype 9 (AAV9), unlike any other known viral vector, are able to cross the blood-brain barrier (BBB) from the bloodstream after intravenous injection in mice and other animals. This feature provides a novel means of homogeneous CNS gene delivery for the treatment of MPS IIIA. Because the human SGSH coding region is small, the number and distribution of vector-transduced cells within the CNS can be maximized by using a derivative of rAAV vectors, self-complementary AAV (scAAV). scAAV vectors bypass the requirement for converting the single-stranded DNA of the parent virus into double-strand DNA for gene expression, and multiply transduction efficiency by orders of magnitude in many tissues.
The specific aims of this proposal are to 1) Compare scAAV and single-strand AAV vectors for hSGSH expression and therapeutic effect in MPSIIIA mice and 2) Test therapeutic efficacy in later stages of the disease to reflect the clinical realities of treatng the MPS IIIA patient population. The rationale for the research strategy is that it combines the novel gene delivery properties of AAV9 with the high efficiency of scAAV and compact promoters to maximize the probability of successfully treating CNS pathology, as well as the relatively milder somatic disorders associated with this disease. The proposed research is significant because it addresses the greatest obstacles to effective gene therapy treatment for a range of neurological disorders. Successful completion of the project is expected to have an immediate impact on the MPS IIIA patient population, with a working therapeutic procedure in hand to advance to the clinical testing process.

Public Health Relevance

The proposed research is relevant to public health because it addresses a fatal genetic disease, Sanfilippo A, for which there is no other treatment, and which poses a significant burden to patient's families, and costs to the health care system. The proposed research uses novel gene delivery technology to achieve effective therapies for diseases of the central nervous system, which is relevant to the NIH's mission to reduce the burdens of human disability.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Porter, John D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Nationwide Children's Hospital
United States
Zip Code
Fu, Haiyan; Cataldi, Marcela P; Ware, Tierra A et al. (2016) Functional correction of neurological and somatic disorders at later stages of disease in MPS IIIA mice by systemic scAAV9-hSGSH gene delivery. Mol Ther Methods Clin Dev 3:16036
Naughton, Bartholomew J; Duncan, F Jason; Murrey, Darren A et al. (2015) Blood genome-wide transcriptional profiles reflect broad molecular impairments and strong blood-brain links in Alzheimer's disease. J Alzheimers Dis 43:93-108