Abstract
The development of new sequencing technologies in the post-genomic era has accelerated the identification of causative mutations of several single gene disorders. Advances in cell and animal models provide insights into the underlining pathogenesis, which facilitates the development and maturation of new treatment strategies. The progress in biochemistry and molecular biology has established a new class of therapeutics—the short RNAs and expressible long RNAs. The sequences of therapeutic RNAs can be optimized to enhance their stability and translatability with reduced immunogenicity. The chemically-modified RNAs can also increase their stability during intracellular trafficking. In addition, the development of safe and high efficiency carriers that preserves the integrity of therapeutic RNA molecules also accelerates the transition of RNA therapeutics into the clinic. For example, for diseases that are caused by genetic defects in a specific protein, an effective approach termed “protein replacement therapy” can provide treatment through the delivery of modified translatable mRNAs. Short interference RNAs can also be used to treat diseases caused by gain of function mutations or restore the splicing aberration defects. Here we review the applications of newly developed RNA-based therapeutics and its delivery and discuss the clinical evidence supporting the potential of RNA-based therapy in single-gene neurological disorders.
Highlights
Over the past 30 years, knowledge of neurogenetics has evolved considerably
Advances in molecular diagnosis and the development of ribonucleic acid (RNA)-based medications reveal a great potential in precision therapy for neurological disorders
For some RNA-based therapies, for example, enzyme replacement therapy, it can have long-lasting effects compared to the traditional small molecule-based drugs where the therapeutic effects are completely governed by its ADME profile
Summary
Over the past 30 years, knowledge of neurogenetics has evolved considerably. Advances in sequencing technology and molecular medicine have led to the identification of many genes that are involved in neurological diseases. Genes are deoxyribonucleic acid (DNA) sequences that are transcribed into RNAs and subsequently translated into proteins This is the central dogma of biological systems—from prokaryotic to eukaryotic cells. A frameshift mutation that is caused by insertion, deletion, or rearrangement of the DNA sequences can disrupt the entire reading frame of a gene as well as introduce a premature stop codon, which results in a severe dysfunctional protein. Haploinsufficiency or loss of function that is caused by the truncated protein is frequently encountered in tumor suppressor proteins (e.g., p53 and PTEN) [3,4] or enzyme deficiencies (e.g., Pompe disease, lysosomal storage disease) [5,6] Another category of mutations is microsatellite repeat expansion (MRE) which is responsible for several neurological disorders. RNA therapy to single-gene neurological disorders in routine clinical practice is on the horizon
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