Huntington's disease future or investigational therapies
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Future or Investigational Therapies
Potential treatments
Trials and research are conducted on Drosophila fruit flies and mice that have been genetically modified to exhibit HD, before moving on to human trials.
Research is reviewed on various websites for HD sufferers and their families, including the Huntington's Disease Lighthouse, Hereditary Disease Foundation, and Stanford HOPES websites. Primary research can be found by searching the National Library of Medicine's PubMed. Clinical trials of various treatments are ongoing, or yet to be initiated. For example, the US registrar of trials has nine that are currently recruiting volunteers.[1]
Intrabody Therapy
Engineered intracellular antibody fragments (intrabodies) have shown efficacy in vivo as therapeutic agents against pathogenic mutant huntingtin protein in fly models of HD. An intracellularly expressed single-chain Fv against the amino-terminal end of mutant huntingtin (mHtt) has been shown to reduce mHtt aggregate formation and increase turnover of the mHtt fragments in tissue culture models of HD.[2][3] In a drosophila HD model, the expression of this anti-HD intrabody rescued fly survival through the larval and pupal stages to adult emergence. Additionally, the intrabody delayed neurodegeneration in the fly model, and significantly increased the mean adult lifespan.[4] The engineered antibody approach shows promise as a tool for drug discovery and as a potential novel therapeutic for other neurodegenerative disorders resulting from protein misfolding or abnormal protein interactions, including Parkinson’s, Alzheimer’s and prion diseases.[5]
Gene silencing
The most hopeful prospective treatment currently studied is based on interrupting the effects of the HD gene within cells ( gene silencing). Since HD is caused by expression of a single gene, it makes an easier target, and silencing it should halt the progression of the disease. Some success has been achieved with mouse models; in a study with a mouse model of HD treated with siRNA therapy achieved 60% reduction knockdown in expression of the gene and progression of the disease was stalled.[6] ,in another study, mouse models in late stages of the disease recovered their motor functions using doxycycline.[7]
Others
Other agents and measures that have shown promise in initial experiments include dopamine receptor blockers, creatine, CoQ10, the antibiotic Minocycline, exercise, antioxidant-containing foods and nutrients, antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors SSRIs, such as sertraline, fluoxetine, and paroxetine) and select dopamine antagonists, such as tetrabenazine.
Living Cell Technologies in New Zealand has attempted pig cell implants in trials with positive results in primates, but has yet to conduct a human trial.[8]
References
- ↑ clinicaltrials.gov
- ↑ Lecerf, J. M., Shirley, T. L., Zhu, Q., Kazantsev, A., Amersdorfer, P., Housman, D. E., Messer, A. & Huston, J. S. Human single-chain Fv intrabodies counteract in situ huntingtin aggregation in cellular models of Huntington's disease. (2001) Proc. Natl. Acad. Sci. USA 98, 4764-4769.
- ↑ Miller, T. W., Zhou, C., Gines, S., MacDonald, M. E., Mazarakis, N. D., Bates, G. P., Huston, J. S. & Messer, A. A human single-chain Fv intrabody preferentially targets amino-terminal huntingtin fragments in striatal models of Huntington's disease (2005) Neurobiol. Dis. 19, 47-56.
- ↑ Wolfgang WJ, Miller TW, Webster JM, Huston JS, Thompson LM, Marsh JL, Messer A. Suppression of Huntington's disease pathology in Drosophila by human single-chain Fv antibodies. (2005) Proc Natl Acad Sci USA 32:11563-8.
- ↑ Miller, T. W., Messer, A. Intrabody Applications in Neurological Disorders: Progress and Future Prospects. (2005) Molecular Therapy. 12, 394-401.
- ↑ Harper SQ, Staber PD, He X; et al. (2005). "RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model". Proc. Natl. Acad. Sci. U.S.A. 102 (16): 5820–5. doi:10.1073/pnas.0501507102. PMID 15811941.
- ↑ Miguel Díaz-Hernández, Jesús Torres-Peraza, Alejandro Salvatori-Abarca, María A. Morán, Pilar Gómez-Ramos, Jordi Alberch, and José J. Lucas (October 19, 2005). "Full Motor Recovery Despite Striatal Neuron Loss and Formation of Irreversible Amyloid-Like Inclusions in a Conditional Mouse Model of Huntington's Disease". The Journal of Neuroscience. 25 (42): 9773–9781. Retrieved 2006-07-16.
- ↑ World health Article