RNAi therapeutics for CNS disorders

doi:10.1016/j.brainres.2010.03.038

Brain Research

Volume 1338, 18 June 2010, Pages 112-121

https://doi.org/10.1016/j.brainres.2010.03.038 Get rights and content

Abstract

RNA interference (RNAi) is a process of sequence-specific gene silencing and serves as a powerful molecular tool to manipulate gene expression in vitro and in vivo. RNAi technologies have been applied to study gene function and validate drug targets. Researchers are investigating RNAi-based compounds as novel therapeutics to treat a variety of human diseases that are currently lacking sufficient treatment. To date, numerous studies support that RNAi therapeutics can improve disease phenotypes in various rodent models of human disease. Here, we focus on the development of RNAi-based therapies aimed at treating neurological disorders for which reduction of mutant or toxic gene expression may provide clinical benefit. We review RNAi-based gene-silencing strategies, proof-of-concept studies testing therapeutic RNAi for CNS disorders, and highlight the most recent research aimed at transitioning RNAi-based therapeutics toward clinical trials.

Introduction

Treatment of neurological diseases affecting the central nervous system (CNS) has proven to be a major challenge for clinicians. As average life span continues to increase among the human population, so does the societal burden caused by age-related neurodegenerative conditions; the two most prominent being Alzheimer's disease (AD) and Parkinson's disease (PD). These diseases, among others, may have known genetic components or may appear sporadically with unknown etiology. By contrast, some neurological disorders [e.g., Huntington's disease (HD) and several spinocerebellar ataxias (SCAs)] are solely caused by the inheritance of genetic mutations. In recent years, there has been considerable progress made in elucidating the pathogenic mechanisms underlying these various neurological diseases; however, there are currently no cures, and therapies are largely symptomatic. Thus, researchers are investigating innovative therapeutic strategies to treat these diseases. One such approach is to silence (i.e., turn off or reduce) the expression of genes that cause or contribute to disease phenotypes. For neurological conditions with more complex origins, the candidate target genes are often less clear; however, gene-silencing strategies may be employed to inhibit cellular pathways that contribute to disease manifestation. For several autosomal dominant neurodegenerative diseases, gene mapping has identified the disease-causing mutations, facilitating candidate target gene selection for therapeutic silencing. Notably, in some cases, researchers have validated therapeutic target genes using tetracycline-regulated transgenic mouse models of dominant neurodegenerative diseases. These inducible models—in which the expression of mutant genes can be turned on or off—serve as powerful tools for assessing the reversibility of neurological conditions and evaluating disease-causing genes as therapeutic targets. For example, using these models, independent groups working on HD and SCA1 demonstrated that neuropathological and abnormal behavioral features of disease developed over time when the respective mutant proteins were expressed (Yamamoto et al., 1984, Zu et al., 2004). However, when transgene expression was turned off in affected mice, disease progression halted and pathological and behavioral features improved. Together, these experiments serve as proof-of-principle studies supporting the notion that inhibiting the expression of disease-causing genes may provide therapeutic benefit in patients already exhibiting disease phenotypes. In recent years, scientists have been rigorously investigating a variety of strategies to selectively inhibit gene expression with high specificity. To date, RNA interference (RNAi), which is capable of gene-specific targeting of messenger RNAs (mRNAs), has shown beneficial effects in cell and animal models.

Section snippets

RNAi overview

RNAi is a natural cellular process that serves to regulate gene expression and provide an innate defense mechanism against viral invasion and transposable elements (McManus and Sharp, 2002). The identification of the RNAi process has been recognized among the most significant contributions to cell biology. In 2006, the Nobel Prize in Physiology or Medicine was awarded to researchers Craig Mellow and Andrew Fire for their crucial role in the discovery of RNAi (Fire et al., 1998). Having been

Tools for RNAi

With a better understanding of endogenous miRNA biogenesis and gene silencing processes, scientists have devised strategies to co-opt the RNAi machinery to specifically silence various genes of interest. In this way, RNAi serves as a powerful molecular tool used to study gene function in biological processes and provides a novel strategy to treat a variety of diseases (e.g., dominant genetic disorders, cancer, and viral invasion, among others). The application of RNAi as a biological or

Proof-of-concept studies testing therapeutic RNAi in the CNS

During the past decade, scientists have made much progress in evaluating RNAi-based therapeutics for diseases affecting the CNS (Table 1). The potential of RNAi therapies has been tested in several cell and animal models of human neurodegenerative disease. The polyglutamine (polyQ)-repeat disease family has been a major focus for testing RNAi-based therapeutics in several laboratories (Caplen et al., 2002, Harper et al., 2005, Kubodera et al., 2005, Li et al., 2004, Xia et al., 2006). There are

Transitioning RNAi toward the clinic

The success of proof-of-concept studies highlights the potential utility of RNAi-based therapeutics for neurological disorders. As a step toward transitioning these strategies to the clinic, experiments to assess the safety, delivery, and dosing of RNAi reagents have been performed. One of the major considerations for gene-silencing applications is specificity. Though many reports endorse the potency and specificity of RNAi-based approaches, the issue remains largely unresolved across tissues

Summary

Since the discovery of RNAi 10 years ago, researchers have made substantial progress in elucidating the machinery and mechanisms involved in this gene silencing pathway. Scientists have used RNAi-based technologies to silence numerous genes in a variety of cell culture and animal models. Encouraging results from several proof-of-concept studies highlight the potential that RNAi therapeutics have for treating numerous disorders, including neurological conditions. Although there are significant

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ReviewRNAi therapeutics for CNS disorders

Abstract

Introduction

Section snippets

RNAi overview

Tools for RNAi

Proof-of-concept studies testing therapeutic RNAi in the CNS

Transitioning RNAi toward the clinic

Summary

Neuron

Brain Res.

Mol. Ther.

Cell

J. Control. Release

Mol. Ther.

Mol. Ther.

J. Biol. Chem.

Cell

Nat. Biotechnol.

Cell

Cell

Exp. Neurol.

Cell

J. Biol. Chem.

Differentiation

Curr. Biol.

Mol. Ther.

Mol. Ther.

Exp. Neurol.

Cell

Mol. Cell.

Cell

Mol. Ther.

Neurosci. Res.

J. Biol. Chem.

Neurobiol. Dis.

Cell

Functional delivery of siRNA in mice using dendriworms

ACS Nano.

Retraction of synapses and dendritic spines induced by off-target effects of RNA interference

J. Neurosci.

Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease

PLoS ONE

3′ UTR seed matches, but not overall identity, are associated with RNAi off-targets

Nat. Methods

Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins

Nucleic Acids Res.

Induction of an interferon response by RNAi vectors in mammalian cells

Nat. Genet.

Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs

Rna

Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference

Hum. Mol. Genet.

Genomewide view of gene silencing by small interfering RNAs

Proc. Natl. Acad. Sci. U.S.A.

Polycistronic RNA polymerase II expression vectors for RNA interference based on BIC/miR-155

Nucleic Acids Res.

Viral vectors for gene delivery to the nervous system

Nat. Rev. Neurosci.

Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits

Proc. Natl. Acad. Sci. U.S.A.

Sustained effects of nonallele-specific Huntingtin silencing

Ann. Neurol.

RNA interference is mediated by 21- and 22-nucleotide RNAs

Genes Dev.

Molecular pathogenesis of Parkinson disease

Arch. Neurol.

A portrait of Alzheimer secretases—new features and familiar faces

Science

Off-target effects by siRNA can induce toxic phenotype

RNA

Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans

Nature

Short-term cytotoxic effects and long-term instability of RNAi delivered using lentiviral vectors

BMC Mol. Biol.

Normal microRNA maturation and germ-line stem cell maintenance requires Loquacious, a double-stranded RNA-binding domain protein

PLoS Biol.

Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes

Nat. Biotechnol.

RNAi-mediated inhibition of cathepsin B and uPAR leads to decreased cell invasion, angiogenesis and tumor growth in gliomas

Review
RNAi therapeutics for CNS disorders