In Utero Gene Therapy

Children'S Hospital Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

[unreadable] DESCRIPTION (provided by applicant): The lysosomal storage diseases are inherited metabolic deficiencies that produce fatal degenerative syndromes affecting multiple organ systems. Studies of bone marrow and neural stem cell transplantation, germline and somatic gene transfer, and injections of purified enzyme have shown that supplying the normal enzyme early in life may significantly reduce pathology compared to treatments initiated at older ages. However, the central nervous system (CNS) has been especially difficult to treat due to the blood-brain barrier. Metabolic diseases that affect the CNS typically have global lesions and gene delivery within the brain has been relatively limited, particularly in large mammals. The goal of these studies is to develop methods to transfer a functional gene into the diseased fetal brain at therapeutic levels in a widely disseminated manner. Early treatment is expected to reduce the severity of pathology later in life or prevent it all together. Animal models with Beta-glucuronidase (GUSB) deficiency, causing mucopolysaccharidosis (MPS) VII (Sly disease), will be studied. We have developed two approaches for delivering the normal gene to the brain side of the blood-brain barrier. 1) Transplanting neural progenitor cells, which migrate extensively in the brain if transplanted during development. We have shown that NSCs differentiate into neurons and glial cells that are indistinguishable from the host brain cells. We will evaluate the fate of the engineered cells, the expression of the transferred GUSB, the long-term effects on pathology, and the safety of the treatments. 2) We have recently found that injection of AAV2 vectors into the cerebral lateral ventricles during development results in wide circulation via the cerebrospinal fluid (CSF) and transduction of many structures. Expression of the transferred cDNA is maintained for extended periods of time. The MPS VII model system is a paradigm for delivering gene products to the brain for other lysosomal storage diseases, in many of which the brain is the most severely compromised organ and will be the primary target for therapy, as well as for other metabolic disorders where global lesions in the brain must be treated. The MPS VII model system is exceptionally well suited for characterizing the engraftment potential of neural progenitor cells and the fate of direct vector transduction, in both the mouse and large animals under actual disease conditions.