Key Points
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More than 20 diseases are caused by expansions of trinucleotide repeats. The expended repeats can be in either coding or non-coding DNA.
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Friedreich ataxia is caused by a non-coding repeat expansion that leads to loss of the protein frataxin, accumulation of iron in mitochondria, increased susceptibility to oxidative stress, and a reduction in oxidative phosphorylation that is due to deficiency in mitochondrial proteins. Antioxidant therapy has had promising results and is currently being investigated in further clinical trials.
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Repeat expansion in the 5′ UTR of the fragile X syndrome gene results in increased DNA methylation, reduced gene transcription and loss of the protein product FMR1. DNA demethylating agents and histone deacetylase (HDAC) inhibitors have had limited success in enhancing transcription in vitro. An antagonist of the group 1 metabotropic glutamate receptor ameliorates the phenotype in a Drosophila model of fragile X syndrome.
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An expanded CTG repeat in the 3′ UTR of the dystrophia myotonica protein kinase (DMPK) gene probably causes the disease manifestations of dystrophia myotonica 1 by sequestering RNA-binding proteins. Ribozyme therapy to splice out the expanded region has had efficacy both in vitro and in vivo. Bioflavonoids can reduce cell toxicity in vitro, possibly through activation of class III HDACs.
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Animal and cell-culture models of polyglutamine diseases show protein aggregation, caspase activation, excitotoxicity, oxidative stress and transcriptional dysregulation. Treatments that are based on these findings have shown efficacy in model systems. Combinatorial therapy using drugs with different targets might yield the most beneficial effects. Definitive therapy that is based on inactivation of the mutant gene still has technical barriers to overcome.
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The triplet repeat expansion disorders have defined genetic defects, well-characterized cell-culture and animal models, and identified disease mechanisms that offer the opportunity for systematic approaches to the development of therapeutics.
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 result in 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.
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Acknowledgements
This work was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of General Medical Sciences (NIGMS) at the US National Institutes of Health. N.A.D. is supported under a clinical pharmacology research associate training fellowship awarded by NIGMS.
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Spinal and bulbar muscular atrophy
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Glossary
- OPEN-LABEL TRIAL
-
A clinical trial in which both subjects and investigators know which drug is being tested and the doses that are being used.
- DOUBLE-BLIND TRIAL
-
A study in which neither the investigator nor the subject know whether a medication or placebo is being used for any given subject, so as to prevent subjective bias on the part of the subject or investigator.
- PLACEBO-CONTROLLED
-
The use of an inactive substance or treatment that seems to be the same as, and is given in the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared with the effects of the placebo.
- PHASE II CLINICAL TRIAL
-
A study that is carried out to obtain more safety data and preliminary data on the effectiveness of the drug for a particular indication in patients with the disease or condition. Phase II studies help to determine the feasibility of larger-scale definitive trials.
- PHASE I CLINICAL TRIAL
-
An initial clinical study that involves small numbers of healthy human volunteers and small doses to assess safety, metabolism and excretion of a drug.
- LYMPHOBLASTS
-
Immature white blood cells.
- DENDRITES
-
Short and typically highly branched extensions of the neuronal cell body that form synaptic contacts with the terminals of other neurons and allow the transmission of nerve impulses between cells.
- MYOTONIA
-
The failure of muscle to relax immediately after voluntary contraction has stopped.
- ANTICIPATION
-
The tendency of certain diseases to have an earlier age of onset and increasing severity in successive generations.
- PROTEASOME
-
A cytosolic protein complex that degrades proteins that have been marked for destruction by the ubiquitylation pathway.
- CORTEX
-
The superficial layer of grey matter that is involved in higher functions, including initiation of voluntary movements, cognition and emotion.
- STRIATUM
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The region of the brain that receives excitatory input from the cortex, thalamus and midbrain. It has a pivotal role in modulating motor activity and higher cognitive function.
- STRIATAL PROJECTION NEURONS
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These are medium sized, GABA-containing neurons of the striatum that project to the substantia nigra and have an important role in the regulation of movement.
- PHASE III CLINICAL TRIAL
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A study that is intended to gather the extra information about effectiveness and safety that is needed to evaluate the overall benefit–risk relationship of the drug. Phase III studies also provide a basis for extrapolating the results to the general population.
- RESVERATROL
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A natural compound that is found in grapes, mulberries, peanuts and other plants or food products, especially red wine, that has antioxidant, antimutagen and anti-inflammatory properties.
- PET SCAN
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A positron emission tomography scan. This is an imaging technique that relies on the detection of γ-rays that are emitted from tissues after the administration of a natural biochemical substance into which positron-emitting isotopes have been incorporated.
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Di Prospero, N., Fischbeck, K. Therapeutics development for triplet repeat expansion diseases. Nat Rev Genet 6, 756–766 (2005). https://doi.org/10.1038/nrg1690
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DOI: https://doi.org/10.1038/nrg1690
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