Sustained Therapeutic Reversal of Huntington's Disease by Transient Repression of Huntingtin Synthesis

Abstract

SUMMARY The primary cause of Huntington’s disease (HD) is expression of huntingtin with a polyglutamine expansion. Despite an absence of consensus on the mechanism(s) of toxicity, diminishing the synthesis of mutant huntingtin will abate toxicity if delivered to the key affected cells. With antisense oligonucleotides (ASOs) that catalyze RNase H-mediated degradation of huntingtin mRNA, we demonstrate that transient infusion into the cerebral spinal fluid of symptomatic HD mouse models not only delays disease progression, but mediates a sustained reversal of disease phenotype that persists longer than the huntingtin knockdown. Reduction of wild type huntingtin, along with mutant huntingtin, produces the same sustained disease reversal. Similar ASO infusion into non-human primates is shown to effectively lower huntingtin in many brain regions targeted by HD pathology. Rather than requiring continuous treatment, our findings establish a therapeutic strategy for sustained HD disease reversal produced by transient ASO-mediated diminution of huntingtin synthesis.

Prion-Like Propagation of Protein Aggregation and Related Therapeutic Strategies

“…ASO-mediated decrease of huntingtin protein in a mouse model of Huntington's disease delayed and even reversed pathology. This effect persisted for months after the mRNA and protein levels of huntingtin returned to baseline, indicating a robust and long-lasting effect [85]. ASOs also decreased mutant SOD1 in both the brain and the CSF in a mouse model of ALS [87].…”

“…These techniques target a highly specific sequence present in the mRNA of a target protein, leading to decreased translation (RNAi) or degradation of the mRNA transcript (RNAi/ASO) [84][85][86]. RNAi techniques can preferentially decrease the expression of a mutant allele over the wild-type transcript, as base pair mismatches between the siRNA and target RNA inhibit their binding and subsequent degradation [86].…”

“…These molecules have some advantages over RNAi-based approaches, as they are readily modified to improve their stability and decrease their susceptibility to exonuclease degradation, leading to increased longevity in vivo. Specific modifications can also improve their solubility and tissue distribution, which will allow for decreased concentrations to be used in vivo [83,85].…”

Hunting for the mutant without the MAP(K)

“…A long-standing idea in HD therapy development has centered around the clearance of mHTT, and previous studies have shown attenuated HD phenotypes upon genetic reduction of mHTT [3]. Recently, substantial progress has been made using anti-sense oligonucleotides (ASOs) to reduce mHTT in preclinical models of HD [4], however, the challenge of delivering ASOs clinically has precluded its widespread use and application. Therefore, pharmacological interventions that can be more easily delivered while similarly reducing mHTT levels are especially appealing.…”

RNA-targeted Therapeutics for ALS

“…ASOs for use outside of the nervous system have been developed for multiple diseases and recently resulted in an US Food and Drug Administrationapproved drug for familial hypercholesterolemia (mipomersen) [18]. The promise of using ASOs to treat neurodegenerative diseases has been greatly bolstered by recent demonstrations of wide spread distribution of ASOs throughout the brain and spinal cord when delivered to the cerebrospinal fluid (CSF) [19][20][21].…”