Sustained effects of nonallele‐specific Huntingtin silencing

Abstract

These data indicate that the coincident silencing of the wild-type and mutant htt may be considered as a therapeutic tool for HD.

Epigenetic Mechanisms of Neurodegeneration in Huntington's Disease

“…Less inclusion and more DARPP32, NeuNpositive cells [122] AAV-miRNA mRNA/inhibition CAG140 knock-in mouse model…”

“…Reduced toxicity compared with AAV-shRNA [123] N171-82Q transgenic mouse Improved behavior and prolonged lifespan [122] siRNA-Cholesterol mRNA/inhibition AAV1/8-HD400aa-100Q-injected mouse Less inclusion and behavior [125] ss-siRNA mRNA/inhibition HdhQ150 knock-in mouse model…”

“…Harper et al [117] showed that RNA interference using adeno-associated virus-small hairpin RNA (shRNA) improves motor deficits and neuropathological phenotypes in a transgenic (N171-82Q) mouse model of HD. Most RNA interference studies using adenovirus-shRNA, lentivirus-shRNA, adeno-associated virus-miRNA, and cholesterol-conjugated siRNA have shown a reduction of mthtt aggregates, improvement of motor behavior, and reduced neuropathological sequelae (Table 1) [118][119][120][121][122][123][124][125].…”

Recent Advances in RNA Interference Therapeutics for CNS Diseases

“…Both viruses are minimally immunogenic and can transduce a number of CNS cell types. Recombinant lentiviruses are pseudotyped with various glycoproteins that can impart different tropisms after directed delivery into brain [47,48], and they have been used successfully in gain-of-function [49] and loss of function studies [50][51][52][53].One difference between lentivirus and AAV or adenovirus-based systems is the level of expression.This is due, in part, because LV-mediated transduction often results in low copy numbers of transgene/cell. Also, the placement of the expression cassette in the LV genome can affect expression levels [54].Most LV vectors integrate unless the integrase activity has been inactivated.As integrase-deficient vectors often have low titers compared with their integrase competent counterparts, their production for use for therapeutic applications is impractical.Integration competency for CNS applications may be less of an issue than in the setting of stem cell transduction (most cells in the CNS are not dividing), where integration and activation of an oncogenic gene provides a growth advantage for the transformed cell [55,56].…”

“…HD is a gainof-function autosomal dominant disease with neuronal dysfunction occurring prior to cell death in medium spiny neurons within the striatum, as well as other brain regions. Patients exhibit involuntary hyperkinetic movements, coordination difficulties, and cognitive disturbances [50,80]. Both nonallele-specific (targeting the mutant and wild type alleles) and allele-specific (targeting only the mutant allele) approaches for HD therapy are under development.…”