In general, genetic disorders are inherited diseases that arise when someone has two dysfunctional copies of a single gene on both of their chromosomes. The result of this is often devastating, resulting in abnormal functioning of specific cells and the development of an often life-threatening condition. In these cases gene therapy is employed to replace the dysfunctional gene with a correct copy and restore the normal functioning of affected cells. In this page we describe some of the most well-known genetic disorders that are being targeted by the gene therapy community.
Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle disorder with an incidence rate of 1:80,000 births in Japan (1). It occurs when a mutant enzyme protein (OTC) impairs the reaction that leads to condensation of carbamoyl phosphate and ornithine to form citrulline. This impairment leads to reduced ammonia incorporation, which, in turn, causes hyperammonemia. Ammonia is especially damaging to the nervous system, so ornithine transcarbamylase deficiency causes neurological problems as well as eventual damage to the liver.
PKU is an autosomal recessive disorder resulting from a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine (figure 1) (1). PAH deficiency is the most common cause of the accumulation of phenylalanine (Phe), called hyperphenylalanemia (HPA), with an incidence of roughly 1:10000 Caucasian live births, with a higher incidence in the populations of Turkey, Ireland and Norway (http://emedicine.medscape.com/article/947781-overview).
A recent article published on the New England Journal of medicine by Aiuti and colleagues reports on the progress of 10 patients that have been treated for ADA-SCID by gene therapy. This is a form of severe combined immuno-deficiency (SCID) where there is a lack of the enzyme adenosine deaminase (ADA), coded for by a gene on chromosome 20.
Duchenne muscular dystrophy (DMD) is an X-linked genetic disease characterized by the absence of dystrophin in the muscle. This large protein of 427 kDa is encoded by a 14 kb mRNA (79 exons) (1). This dystrophin protein is located under the membrane of the muscle fiber and interacts with other trans-membrane proteins. It is needed to insure mechanical stress resistance during muscle contraction. The lack of dystrophin weakens the sarcolemma and thus makes fibers less resistant to stress. When a fiber is damaged, the satellite cells (stem cells located near the muscle fibers) are activated and proliferate to allow fiber regeneration (2). In the case of a DMD patient, fibers are frequently damaged due to the lack of dystrophin. The regeneration is also ensured by the proliferation of satellite cells though their number decreases rapidly and when there are no more satellite cells, the average diameter and the number of fibers progressively decrease bringing the development of fibrosis and fat infiltrations into the muscles. There is currently no treatment for DMD and life expectancy is between 20 to 25 years of age.