Nucleic Acid-Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Abstract

The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid-based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood-brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with "common" diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of "common" disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders.

Keywords: antisense oligonucleotide; gene therapy; neurological disorder; noncoding RNA; orphan disorder; siRNA.

FIGURE 1

Innovations in NBT chemistry. PD: oligonucleotides with phosphodiester bond (natural DNA/RNA); PS: phosphorothioate bond; NP: N3’-->P5’ phosphoramidate bond; NPS: N3'-->P5′ thio-phosphoramidate bond; LNA: locked nucleic acid unit; PMO: phosphorodiamidate Morpholino oligomer; TNA: α-l-threose-based; A, G: nucleotide bases; R: currently used 2′O modifications of the sugar moiety.

FIGURE 2

Novel biological mechanisms accessible through NBTs. (A) Modulation of splicing; SP: spliceosome components; ASO: antisense oligonucleotides. (B) Modulation of miRNA activity. (C) Small activating RNAs (saRNA). (D) Modulation of natural antisense transcript (NAT) activity; RNApol: RNA polymerase. (E) Extra-coding RNA (ecRNA); DNMT1: DNA methyl transferase 1. (F) Enhancer RNAs (eRNA); negative elongation factor complex (NELF); CBP: histone acetyltransferase CREB-binding protein.