Synthetic Nucleic Acids and Treatment of Neurological Diseases

Abstract

M ost drugs are small molecules and are less than 500 Da in molecular weight. 1 Small molecules are effective when targeting an enzyme active site or a ligand binding site within a receptor because they can fit snugly into molecular pockets and effectively block key functions. However, some proteins have multiple functions or lack binding pockets capable of forming adequate interactions. These proteins are sometimes referred to as "undruggable." While it might be more accurate to refer to them as "undrugged," they nevertheless offer serious challenges to drug development and demand innovative approaches to drug discovery. 2 In other cases, lack of a protein is the problem rather than too much. For these diseases, the use of small molecules will sometimes be problematic because there is no clear rationale as to why a small molecule should increase expression or activity of a specific gene.This review highlights the potential for antisense oligonucleotides (ASOs) 3 to complement the development of small molecule drugs. Antisense oligonucleotides are currently being developed for diseases, such as Duchenne muscular dystrophy, 4 Huntington disease, 5 and spinal muscular atrophy, 6,7 for which few treatment options currently exist. This review will begin by describing ASO technology, its mechanism, and clinical history. It will then focus on case studies for applying ASOs to gene regulation for neurological disease.Question What is the status of using oligonucleotides to modulate gene expression for the treatment of neurological diseases?Findings Work using oligonucleotides to modulate expression of frataxin and survival motor neuron proteins demonstrates progress in both the basic and clinical science.Meaning The significance of oligonucleotides as a treatment strategy for neurological diseases is likely to increase.

Recent advances in antisense oligonucleotide therapy in genetic neuromuscular diseases

“…Hybridization of ASO to the intracellular target mRNA can result in specific inhibition of gene expression by two main mechanisms. [ 13 14 15 ] The most common mechanism is by induction of endogenous RNAse H activity (ASO-RNase H) that cleaves the mRNA-ASO hetero-duplex, for example. This leads to degradation of the target toxic mRNA while leaving the ASO intact.…”

“…[ 9 13 14 15 18 ] In this context, ASO can be used to modulate the ratio of splicing variants or correct spicing defects, by either inducing exon-skipping or exon-inclusion. [ 13 14 15 18 19 20 21 ] Most notably, these advances have been made for neuromuscular diseases, such as SSO technology in SMA[ 7 13 14 15 ] and DMD. [ 19 20 21 ] These two therapeutic technologies are discussed in the following section.…”

New Reasons to Pursue the Therapeutic Potential of Synthetic Nucleic Acids for Neurological Diseases

“…In this issue of JAMA Neurology , Dr. David Corey presents the current state of synthetic nucleic acids as therapeutic agents for several neurological diseases stemming from different types of genetic mutations 1 . Also in the review, Dr. Corey highlights details in the advancement of oligonucleotide therapy for two neurological diseases, Friedreich’s ataxia (FRDA) and spinal muscular atrophy (SMA), which are in discovery and clinical stages of development, respectively.…”

“…Two ASOs mentioned in Dr. Corey’s review for SMA (Nusinersen) and Duchenne’s muscular dystrophy (DMD) (Eteplirsen/AVI-4658) also act by redirecting splicing of the mutated gene, which results in expression of the corrected protein. Both of these candidates are in various stages of clinical trials 1,5 .…”

“…Off-target effects remain a major obstacle in the development of synthetic nucleic acids as therapeutic agents 1 . In the case of FRDA, it appears that a minimum of two conditions are necessary for the formation of R-loops at the GAA tract that help mitigate potential off-target effects: 1) the sequence must be transcribed and 2) must meet a certain length threshold for stable R-loop formation.…”