Neurogene Therapy for the 21st Century

Abstract

Clinical descriptions of a spate of hereditary neurological conditions, including Tay-Sachs disease, Gaucher disease, Fabry disease, and Niemann-Pick disease, appeared in the late 19th and early 20th centuries. The accumulating toxic sphingolipids in Gaucher disease and Niemann-Pick disease were identified in the 1930s and those in Tay-Sachs disease and Fabry disease in early 1960s. Specific enzymatic abnormalities were elucidated in each of these conditions between 1965 and 1969. 1-6 Diagnostic tests based on assaying the respective enzymes were developed using white blood cells, cultured skin fibroblasts, and serum. These assays also provided for the identification of the majority of the carriers of these disorders. Prenatal detection of each of these conditions was established in the early 1970s. 7-9 Genetic counseling for Tay-Sachs disease has reduced the number of cases by approximately 90%. Soon after the metabolic defects were elucidated in Gaucher disease and Niemann-Pick disease, consideration was given to enzyme replacement therapy. 10 In the early 1970s, single infusions of several of the required enzymes revealed reductions of the accumulating lipids in the blood and in the liver. 11-13 No clinical improvement was apparent, and none of these enzymes reached the brain. In the late 1980s, large quantities of purified glucocerebrosidase, the enzyme that is lacking in Gaucher disease, became available. By modifying the glycoform of this enzyme, it was effectively targeted to lipidstoring macrophages. Enzyme replacement with this preparation has brought great benefit to thousands of patients with type 1 Gaucher disease 14 and some help to patients with type 3 (chronic neuronopathic) Gaucher disease. 15 The central nervous system manifestations in patients with type 2 (acute neuronopathic) Gaucher disease have not responded to intravenously administered glucocerebrosidase. Therefore, my colleagues and I 16 developed a technique for the intracerebral administration of this enzyme. If this strategy proves effective, it will be explored in a number of hereditary disorders that involve the central nervous system. Reliable methods will appear in the 21st century to deliver therapeutic enzymes to the central and peripheral nervous systems. Many hereditary neurological disorders will be treated effectively. The effectiveness in gene and neuronal stem cell therapy trials that were initiated in the late 1990s will be greatly improved. One can confidently anticipate that complete cures for many neurogenetic disorders will be developed in the next century.