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ENSAYOS Y ARTICULOS

martes, 6 de noviembre de 2012

NUEVA TERAPIA EN ENF DE HUNTIGTON

Clinical Implications of Basic Research
Hunting Down Huntingtin
Neil Aronin, M.D., and Melissa Moore, Ph.D.
N Engl J Med 2012; 367:1753-175
4November
The treatment of neurodegenerative diseases is an unsolved challenge in modern medicine. Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis mostly manifest as sporadic disorders; the exceptional patient inherits the disease. On the other hand, Huntington's disease (involving dementia, depression, chorea, and years of high-cost care) is an autosomal dominant disease, caused by expansion of a CAG repeat in series near the beginning of the coding region in the gene that encodes huntingtin protein. The mutation results in a messenger RNA (mRNA) with more than 36 repeats and a protein with more than 36 tandem glutamines. Knocking down the mutant huntingtin allele by RNA silencing should be therapeutic; a recent study by Kordasiewicz et al.1 supports a strategy for putting this into practice.
Two technologies for RNA silencing have emerged: the use of antisense oligonucleotides and RNA interference.2 In the former, regions of DNA within an antisense oligonucleotide base pair with the mRNA target, and then a cellular enzyme, RNase H, cleaves the RNA strand of the duplex, thereby degrading the mRNA. Kordasiewicz and colleagues used antisense oligonucleotides to knock down mutant huntingtin in several mouse models of Huntington's disease.3 Treatment with antisense oligonucleotides lowered levels of mutant huntingtin and improved a variety of aberrant behaviors. Reducing the amount of mutant huntingtin was a welcome finding. That the healthful effect lasted for many months beyond cessation of the delivery of antisense oligonucleotides was a surprise and even more welcome.
How might 2 weeks of infusion of antisense oligonucleotides into the cerebrospinal fluid (CSF) reverse or prevent disease for many months? One possibility is that antisense oligonucleotides are hardy and that therapeutic levels last for months. However, the concentration of antisense oligonucleotides diminished long before the salubrious effects waned. Perhaps only a few molecules of antisense oligonucleotides are required to recruit RNase H to mutant huntingtin mRNA. This is an intriguing explanation for antisense oligonucleotide therapy and RNA interference. Both antisense oligonucleotides and small interfering RNA molecules (which actuate RNA interference) are free to attack many mRNA molecules over time.
We propose another explanation (Figure 1Figure 1
Strategy to Treat Huntington's Disease.). Although mutant huntingtin mRNA and protein are expressed in fetal brain,4 in most patients Huntington's disease becomes clinically detectable between 30 and 40 years of age. Mutant huntingtin (or its mRNA) retains some normal function; patients who are homozygous for the mutated gene do not have more severe disease than those with a single mutant allele with the same length of CAG trinucleotide-repeat expansion.5 Thus, the changes wrought by mutant huntingtin are subtle and increase over time. We believe there is a threshold effect. Before disease onset, normal cellular survival systems keep the cellular content of mutant huntingtin below the threshold for disease. Once the threshold is exceeded, progression of disease ensues. So in theory, any treatment that lowers the levels of mutant huntingtin RNA would achieve the same therapeutic effect.
Even important studies have caveats. The mouse models used by Kordasiewicz and colleagues express high steady-state amounts of mutant huntingtin, so the limit of huntingtin knockdown to establish safety is not yet clear. Noteworthy is that 75% knockdown in normal mice did not lead to obvious behavioral changes. We do not know whether this margin of safety applies to humans. Neuropathological studies showed less brain shrinkage in the animals treated with antisense oligonucleotides. It would be useful to know the cell type or types (neuron, glia, microglia) that take up antisense oligonucleotides as well as the overall health of the brain cells. Infusion of the antisense oligonucleotides into the CSF of rhesus monkeys was followed by uptake of the compounds by areas of the cortex that are affected in patients with Huntington's disease, but the striatum (critical in Huntington's disease) and certain other brain regions showed little uptake. Furthermore, the limit in humans for safe silencing of both huntingtin alleles has not been established. It may be more prudent to knock down just the mutant allele while preserving normal huntingtin, whether by antisense oligonucleotide therapy or RNA interference.
Delivery is the biggest issue for all gene-silencing approaches, and an advance in transporting small molecules from the vasculature across the blood–brain barrier might facilitate treatment in brain disease. Microvesicles called exosomes, when injected intravenously, can deliver small RNAs into brain. Adeno-associated viruses administered to the circulation can enter neurons and glia and, pending suitable engineering, could result in long-term expression of small interfering RNAs. The most effective treatment might well combine long-term huntingtin knockdown in the striatum (by means of virally delivered small interfering RNAs) and periodic administration of antisense oligonucleotides to the CSF of the spinal cord.

Source Information
From the RNA Therapeutics Institute and the Neurotherapeutics Institute, University of Massachusetts Medical School, Worcester (N.A., M.M.), and the Howard Hughes Medical Institute, Chevy Chase, MD (M.M.).


References

1 Kordasiewicz HB, Stanek LM, Wancewicz EV, et al. Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis. Neuron 2012;74:1031-1044
.2 Sah DWH, Aronin N. Oligonucleotide therapeutic approaches for Huntington disease. J Clin Invest 2011;121:500-507
.3 Hu X-H, Yang XW. “Huntingtin Holiday”: progress toward an antisense therapy for Huntington's disease. Neuron 2012;74:964-966
.4 Bhide PG, Day M, Sapp E, et al. Expression of normal and mutant huntingtin in the developing brain. J Neurosci 1996;16:5523-5535
.5 Wexler NS, Young AB, Tanzi RE, et al. Homozygotes for Huntington's disease. Nature 1987;326:194-197

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