IMAGE: Huntington’s disease is due to a fault (a repeat of DNA) on chromosome 4. This repetition of genetic information results in the production of an abnormal protein called huntingtin,. Mutant huntingtin aggregates in clusters in the nuclei of certain neurons in the brain, particularly the striatum, a brain structure involved in controlling movement. These neurons degenerate and eventually die, explaining the appearance of abnormal movements. Then huntingtin accumulates in the nuclei of neurons in the cerebral cortex also causing neuronal degeneration with consequent cognitive impairment (memory, attention …) and psychiatric disorders.
A drug that would be the first to target the cause of Huntington’s disease (HD) is effective and safe when tested in mice and monkeys. A study to test the drug in humans has begun. Huntington’s disease is a rare, hereditary disease that causes uncontrolled movements, loss of intellectual abilities, emotional problems and eventually death. The disease is passed from parent to child through a mutation in the huntingtin gene. The mutation results in the production of a disease-causing huntingtin protein. Each child has a 50/50 chance of inheriting the gene mutation. Everyone who inherits the mutated gene will eventually develop the disease.
The new drug, called IONIS-HTTRx, is an antisense drug that acts as a “gene silencer” to inhibit the production of huntingtin protein in people with Huntington’s disease. “Right now we only have treatments that work on the symptoms of the disease.” Leavitt notes the drug is still years away from being used in human clinical practice.
Earlier studies in mouse models of Huntington’s disease showed that treatment with antisense drugs delays disease progression and results in sustained reversal of the disease phenotype. In YAC128 mice, a transgenic model of HD, motor deficits improved within 1 month of initiating antisense treatment and were restored to normal at 2 months after treatment termination. Motor skills of antisense-treated BACHD mice, another transgenic model of HD, improved 8 weeks after initiation of treatment and persisted for at least 9 months after treatment termination. In monkeys, dose-dependent reductions in HTT mRNA and Htt protein throughout the central nervous system were observed after intrathecal administration of an antisense drug. Reduction of cortical huntingtin levels by 50% was readily achieved in monkeys and correlated with 15 to 20% reduction in the caudate. In further tests in rodents and monkeys, IONIS-HTTRx was found to be well-tolerated without any dose-limiting side effects.
The drug is now in a Phase 1/2a clinical study. The drug is delivered into the CSF via an intrathecal injection in the lumbar space, as antisense drugs do not cross the blood brain barrier. In the current clinical study, the drug is administered in 4 doses at monthly intervals. Different doses of the drug will be evaluated for safety and tolerability. In addition, drug pharmacokinetics will be characterized and effects of the drug on specific biomarkers and clinical outcomes will be examined.
http://www.eurekalert.org/pub_releases/2016-02/aaon-ptf022216.php
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