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THERAPEUTICS DEVELOPMENT FOR TRIPLET REPEAT EXPANSION DISEASES
Nicholas A. Di Prospero and Kenneth H. Fischbeck
Abstract | The underlying genetic mutations for many inherited neurodegenerative disorders have been identified in recent years. One frequent type of mutation is trinucleotide repeat expansion. Depending on the location of the repeat expansion, the mutation might resultin a loss of function of the disease gene, a toxic gain of function or both. Disease gene identification has led to the development of model systems for investigating disease mechanisms and evaluating treatments. Examination of experimental findings reveals similarities in disease mechanisms as well as possibilities for treatment.
a result of increasing insights into the pathophysiology of repeat expansion. Here we present current approaches to the development of therapeutics for repeat expansion disorders, with an emphasis on the most intensely studied disorders with preclinical and/or clinical data.
Non-coding trinucleotide repeat disorders
Non-coding expanded repeats include CGG, GCC, GAA, CTG and CAG. The type of repeat and its location within the gene defines each disorder and its pathophysiology. Because these disorders might result from a loss of function, one approach to treatment is through gene replacement, although as more becomes known about the normal function of the relevant gene products, new targets for compensatory intervention are being identified.
Friedreich ataxia. Friedreich ataxia (FA) is the most common inherited ataxia TABLE 1. Most patients
have a homozygous GAA-repeat expansion within the first intron of the frataxin gene, which results in a deficiency of frataxin mRNA and protein. Frataxin levels are inversely correlated with the length of the GAA repeat in the shorter of the two alleles that are carried by the patient3. Loss of frataxin leads to accumulation of mitochondrial iron, increased
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3705, USA. Correspondence to N.A.D. e-mail: [email protected] doi:10.1038/nrg1690
Simple sequence repeats occur throughout the human genome. In 1991 an expansion of one of these repeats, a trinucleotide (CAG) repeat in the gene that encodes the androgen receptor, was discovered in patients with a neurodegenerative disorder: spinal and bulbar muscular atrophy (SBMA)1. The repeat, which normally consists of 1330 CAGs, lengthens to 40 or more CAGs in patients with this disease. Over the few years that...