Mucopolysaccharidosis type I (MPS I), resulting from the deficiency of alpha-L- iduronidase (IDUA), is one of the most common lysosomal storage diseases (LSD) affecting the central nervous system (CNS), which cannot be cured by current treatments. We have shown that lentiviral vector (LV)-mediated gene delivery can produce sustained supraphysiological IDUA levels in plasma and may be therapeutic in treating CNS manifestations if the blood-brain barrier (BBB) can be overcome. The utilization of the endogenous receptor-mediated transcytosis system on BBB-forming brain capillary endothelium will enable rapid and wide delivery of neurotherapeutics across the BBB via circulation. The overall goal of the work proposed is to develop a novel therapeutic approach utilizing low-density lipoprotein receptor family (LDLRf)- mediated transcytosis for fusion protein delivery across the BBB via LV-mediated gene transfer in the liver and/or the HSC for the treatment of CNS manifestations in MPS I. We will identify, by in vitro and in vivo evaluation, the optimal LDLRf-binding domain of apoE for most efficient BBB transport while retaining the normal catalytic function and lysosomal enzyme trafficking of fusion IDUA (Specific Aim 1). The spatial and temporal protein distribution profile will be studied in the CNS and peripheral organs, targeting the liver or HSC-derived erythroid cells as depot organ for tissue-specific transgene production in mice with different ages (Specific Aim 2). Preclinical evaluation will be conduced in a murine MPS I model to identify window of CNS treatment by GAG assay for metabolic correction, pathology evaluation for CNS normalization and behavioral assessments for improvement of CNS functional deficits (Specific Aim 3). Taken together, these studies will not only lead to the development of a novel approach for the treatment of neurological diseases, such as in MPS I, with lifelong BBB-targeted protein delivery, but also provide important knowledge of in vivo changes in receptor-mediated BBB transport system with aging or under pathological conditions.

Public Health Relevance

Narrative The blood-brain-barrier has hindered the capability of rapid and wide delivery of neurotherapeutics and diagnostic agents to the central nervous system. The studies described in this application will open the door to novel approaches for the treatment of neurological disorders-from MPS type I to major public health concerns such as stroke and Alzheimer's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GTIE-A (01))
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cincinnati Children's Hospital Medical Center
United States
Zip Code
Dai, Mei; Han, Jingfen; El-Amouri, Salim S et al. (2014) Platelets are efficient and protective depots for storage, distribution, and delivery of lysosomal enzyme in mice with Hurler syndrome. Proc Natl Acad Sci U S A 111:2680-5
El-Amouri, Salim S; Dai, Mei; Han, Jing-Fen et al. (2014) Normalization and improvement of CNS deficits in mice with Hurler syndrome after long-term peripheral delivery of BBB-targeted iduronidase. Mol Ther 22:2028-37
Wang, Daren; El-Amouri, Salim S; Dai, Mei et al. (2013) Engineering a lysosomal enzyme with a derivative of receptor-binding domain of apoE enables delivery across the blood-brain barrier. Proc Natl Acad Sci U S A 110:2999-3004
Pan, Dao; Kalfa, Theodosia A; Wang, Daren et al. (2011) K-Cl cotransporter gene expression during human and murine erythroid differentiation. J Biol Chem 286:30492-503
Pan, Dao (2011) Cell- and gene-based therapeutic approaches for neurological deficits in mucopolysaccharidoses. Curr Pharm Biotechnol 12:884-96
Wang, Daren; Zhang, Wei; Kalfa, Theodosia A et al. (2009) Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. Proc Natl Acad Sci U S A 106:19958-63