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.

Natural antisense transcripts as drug targets

“…For each therapeutic goal, the modulation of relevant RNA targets may be achieved using multiple therapeutic targets and NBT modalities. For example, several different therapeutic modalities are currently being pursued in spinal muscular atrophy, including gene therapy, therapeutic mRNA delivery, small molecule modulators of splicing and ASOs targeting different biological mechanisms (Table 1, 2; Khorkova et al, 2021).…”

The Medicinal Chemistry of Artificial Nucleic Acids and Therapeutic Oligonucleotides

“…The frequency and duration of the seizures also decreased. The TY777 was named milasen after the name of the patient (Mila) [ 201 , 202 , 203 ].…”

LncRNA: A Potential Target for Host-Directed Therapy of Candida Infection

“…In human diseases, lncRNAs have been identified to play critical regulatory roles in diverse biological process, which afford legible targetable key sites for subsequent modulating. Clinical trials based on nucleic therapies are also being conducted [ 226 ]. Different from other RNA molecules, lncRNAs exhibit highly specific expression patterns in the cell, organ, and spatiotemporal distribution [ 227 ].…”