We have developed a platform strategy to treat the CNS manifestations of lysosomal storage disorders using adeno-associated virus (AAV)-mediated gene transfer. In a now completed NINDS grant (U01 NS047458), we have developed a 2nd generation AAV vector (AAVrh.10) that has markedly improved distribution of gene expression throughout the CNS. The AAVrh.10 vector has already been administered to the human CNS for late infantile neuronal ceroid lipofuscinosis (LINCL;a 1o grey matter disease). We now propose a milestone driven project to apply our experience with LINCL to metachromatic leukodystrophy (MLD), an autosomal recessive lysosomal storage disorder caused by a deficiency in arylsulfatase A (ARSA). Different from LINCL, ARSA deficiency is a grey and white matter disorder resulting from lysosomal accumulation of sphingolipid cerebroside 3-sulfate (""""""""sulfatide"""""""") in the CNS resulting in a widespread demyelination, rapid neurologic decline, a vegetative stage and death a few years after diagnosis. In this project, we propose to develop sufficient preclinical efficacy data and toxicology data to obtain an allowed Investigational New Drug (IND) for the treatment of MLD by direct administration to the CNS of an AAVrh.l0-based vector coding for ARSA. In this revised UOI proposal, with extensive changes based on the recommendations of the reviewers, our overall goal therefore is to complete the preclinical efficacy, toxicology, manufacturing and regulatory requirements necessary to commence a human clinical study. We propose to achieve this goal with the following aims.
Specific Aim 1. Utilizing a scalable manufacturing process, produce and qualify the AAVrh.l0 ARSA vector for the toxicology and clinical studies.
Specific Aim 2. Assess toxicology, immune responses and ARSA distribution following AAVrh.l0-mediated ARSA administration to brain of rats and nonhuman primates.
Specific Aim 3. Develop the clinical protocol and regulatory documents, and gain regulatory approvals for a clinical study.

Public Health Relevance

Metachromatic leukodystrophy (MLD) is a rare, fatal disorder of the brain of children caused by inheritance of an abnormal arylsulfatase A (ARSA) gene. We propose pre-clinical studies to develop an adeno-associated virus gene therapy-based strategy to transfer the normal ARSA gene to the brain to treat MLD. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Rosenberg, Jonathan B; Kaminsky, Stephen M; Aubourg, Patrick et al. (2016) Gene therapy for metachromatic leukodystrophy. J Neurosci Res 94:1169-79
Rosenberg, Jonathan B; Sondhi, Dolan; Rubin, David G et al. (2014) Comparative efficacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates. Hum Gene Ther Clin Dev 25:164-77