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.
Highlights
In recent years, nucleic acid–based therapeutics (NBTs), including antisense oligonucleotides (ASOs), siRNA, shRNA, and viral expression constructs, are becoming more mainstream in drug development
Further advances in viral vector design and understanding of the disease pathophysiology allowed to move the gene therapy for Canavan disease (CD) closer to the clinical stage (Canavan Disease). This early work formed the basis for BBP-812, an AAV9 vector known to cross blood–brain barrier (BBB) developed by Aspa/BridgeBio in collaboration with UMASS Medical School, for the treatment of CD currently in the IND-enabling preclinical stage (BBP-812, 2020)
Better knowledge of the physiology and natural history of orphan diseases will be instrumental in biomarker identification and the choice of optimal methods for clinical monitoring for adverse events after NBT treatment
Summary
Nucleic acid–based therapeutics (NBTs), including antisense oligonucleotides (ASOs), siRNA, shRNA, and viral expression constructs, are becoming more mainstream in drug development. NBTs could be designed to highly selectively target closely related proteins, specific alleles, isoforms, and even point mutations Due to their simplified development cycle that benefits from the rational design process, NBTs are well suited for the treatment of orphan genetic diseases. PS and otherwise chemically modified nucleic acids have extended tissue half-life in the brain due to the low nuclease content of the CSF and are readily taken up by cells, they do not penetrate BBB to a significant extent This necessitates intracerebral, ICV, or IT administration in the clinic. DsRNA-based NBTs used to access siRNA or saRNA mechanisms require a chemical carrier for efficient delivery to cells Due to these considerations, the work on chemical modification of NBTs continues to further improve NBT bioavailability, targeting to specific cell types and BBB penetration. We briefly review some of the latest developments in NBT chemistry below
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