Introduction: Mucopolysaccharidoses (MPS) are a family of lysosomal disorders caused by mutations in genes that encode enzymes involved in the catabolism of glycoaminoglycans. These mutations affect multiple organ systems and can be particularly deleterious to the nervous system. At the present time, enzyme replacement therapy and hematopoietic stem-cell therapy are used to treat patients with different forms of these disorders. However, to a great extent, the nervous system is not adequately responsive to current therapeutic approaches. Areas covered: Recent advances in gene therapy show great promise for treating MPS. This article reviews the current state of the art for routes of delivery in developing genetic therapies for treating the neurologic manifestations of MPS. Expert opinion: Gene therapy for treating neurological manifestations of MPS can be achieved by intraventricular, intrathecal, intranasal and systemic administrations. The intraventricular route of administration appears to provide the most widespread distribution of gene therapy vectors to the brain. The intrathecal route of delivery results in predominant distribution to the caudal areas of the brain. The systemic route of delivery via intravenous infusion can also achieve widespread delivery to the CNS; however, the distribution to the brain is greatly dependent on the vector system. Intravenous delivery using lentiviral vectors appear to be less effective than adeno-associated viral (AAV) vectors. Moreover, some subtypes of AAV vectors are more effective than others in crossing the blood-brain barrier. In summary, the recent advances in gene vector technology and routes of delivery to the CNS will facilitate the clinical translation of gene therapy for the treatment of the neurological manifestations of MPS.
Bibliographical noteFunding Information:
The authors were supported by the National Institutes of Health (5P01HD032652, U54NS065768, and T32 DE007 288). The Lysosomal Disease Network is a part of the National Institutes of Health (NIH) Rare Diseases Clinical Research Network (RDCRN), supported through collaboration between the NIH Office of Rare Diseases Research (ORDR) at the National Center for Advancing Translational Science (NCATS), the National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. RS McIvor and PB Hackett are founders of Discovery Genomics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
© 2014 Informa UK, Ltd.
- Enzyme replacement therapy
- Gene therapy
- Hunter syndrome
- Hurler syndrome
- Sanfilippo syndrome