Gene Therapy for Tay-Sachs and Sandhoff diseases

点击翻译按钮获取中文摘要

Gene Therapy for Tay-Sachs and Sandhoff diseasesOur aim is to treat the genetic problem that causes relentless and lethal neurodegenerative diseases (Tay-Sachs and Sandhoff diseases - termed GM2 gangliosidosis) in young people. A radical approach is needed because lysosomal diseases, of which GM2 gangliosidosis is a classical prototype, account for nearly half the burden of progressive intellectual and neurological deterioration diagnosed in UK children. No effective treatment is known and the caseload burden of progressive intellectual and neurological deterioration identified in 1164 children in the United Kingdom has immense human and societal costs. About 70 lysosomal diseases are known - two-thirds of which damage the brain. The importance of lysosomal disorders has recently been shown by the discovery that defective lysosomal function predisposes to Parkinsonism, thus investing this small cellular particle with central importance in the brain and neurodegenerative diseases which are prevalent in many communities. Over 15 years of intensive scientific research we have perfected gene transfer to the living mammalian brain: we use agents (inactivated passenger viruses that do not cause disease), shown by others to be safe in humans, in efforts to advance treatment for such conditions. Deficient lysosomal components have the special advantage that gene transfer can be used to treat a small focus of tissue but the corrective factor is secreted from this target to be taken up by cells far away. In this way, inoculation of the vector for gene therapy into the brain on a single occasion can rescue the function of a large field of brain tissue and so greatly improve survival in young animals that would otherwise be moribund within a few months. We justify our plans in these studies to translate our previous research findings into patients because we have found that function of an essential enzyme in brain lysosomes can be maintained throughout the entire central nervous system (brain and spinal cord). Moreover, definitive correction of the defect resolves the disease hallmarks and prevents critical loss of brain cells, which cannot otherwise be replaced. Outcomes are optimal when gene therapy is given early.We will develop Investigational Medicinal Products for first-into-human gene transfer studies as part of a clinical trial; there will be a single procedure by a neurosurgeon skilled in the safe administration of treatments to brain structures. This will involve generating effective treatments that can be tested for the first time in living human patients known to afflicted by GM2 gangliosidosis. Our trial will be based on our proof-of-concept studies with correction over years of the disease in Tay-Sachs and Sandhoff diseases authentically modelled in living animals; it will explore safety and early signs of effectiveness (phase I/II clinical trial). A successful outcome would advance treatment for stricken children and young persons with this disease as well as patients affected by other, more familiar and prevalent neurodegenerative diseases.