Huntington’s Disease and Gene Therapy

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Huntington’s Disease and Gene Therapy

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that results in the mutation of the huntingtin (Htt) protein (1) (Zuccato et al., 2010). HD results from the repetition of trinucleotide sequence CAG coding for glutamine which clinically presents with progressive chorea, dementia and psychiatric disturbances (2) (Leegwater-Kim and Cha, 2004) as well as planning and memory impairment (3)(Mrzljak and Munoz-Sanjuan, 2013). Pathologically, HD includes extensive degeneration of medium spiny neurons (4) (Benraiss and Goldman, 2011) and reactive gliosis (2), where astrocytes undergo changes in response to injury or disease (5)(Sofroniew, 2009), in the striatum as well as loss of pyramidal neurons in a number of cortical regions (3)(Mrzljak and Munoz-Sanjuan, 2013). The elongation polyglutamine residues near the N-terminus of Htt causes a mutant conformation of the protein (mHtt) that is transferred to the nucleus where it forms aggregates or inclusions (2)(Leegwater-Kim and Cha, 2004) that result in beta-sheet formation (6)(Kanazawa, 2006). Many researchers have targeted the CAG repeat as a therapy, or even cure, for the disease.

RNA Interference (RNAi):

Antisense mediated gene silencing is the post-transcriptional silencing of genes using antisense molecules that are complementary to the base pairs of the targeted mRNA strand (7)(Nielsen and Nielsen, 2013). The antisense molecules supress translation or lead to direct degradation of the targeted strand (7)(Nielsen and Nielsen, 2013). In doing this it decreases the amount of the protein that would have been formed and in the case of HD improves the symptoms (7)(Nielsen and Nielsen, 2013).

RNAi is a regulatory mec...

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...Conoughey et al., 2010)

The main therapies being explored in the search for a treatment for Huntington’s disease involve the use of RNA interference and antisense therapy. Rather than treating symptoms these therapies are aimed at upstream mechanisms that directly affect the mutant protein involved and, therefore, treat the illness as a whole. A number of challenges present with the use of this type of therapy, many of which have hindered the progression in research. These include endogenous RNA competition, immune response activation and off-target effects (21)(Harper, 2009). Other challenges faced are delivery modes for the RNA molecules and transport or distribution to and from the target site.

However, with the advancement of identifying SNPs and other molecules mHtt that specifically target mHtt, it is only a matter of time before trials reach human models

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