Abstract
Recent advances in the generation, purification and cellular delivery of RNA have enabled development of RNA-based therapeutics for a broad array of applications. RNA therapeutics comprise a rapidly expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. In this review we discuss general concepts of different classes of RNA-based therapeutics, including antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and messenger RNA. Furthermore, we provide an overview of the RNA-based therapies that are currently being evaluated in clinical trials or have already received regulatory approval. The challenges and advantages associated with use of RNA-based drugs are also discussed along with various approaches for RNA delivery. In addition, we introduce a new concept of hospital-based RNA therapeutics and share our experience with establishing such a platform at Houston Methodist Hospital.
Highlights
RNA Therapeutics comprise a rapidly expanding category of drugs that will speed solutions to the clinic; will actualize personalized medicine; and will make the term “undruggable” obsolete
The development of RNA drugs has largely focused on two approaches: (1) antisense RNA (RNAi), where short oligonucleotides recognize and hybridize to complementary sequences in endogenous RNA transcripts and alter their processing (Stephenson and Zamecnik, 1978; Shen and Corey, 2018); and (2) message RNA, where messenger RNAs (mRNAs) encoding certain peptides or proteins elicit their transient expression in the cytoplasm (Wolff et al, 1990; Ulmer and Geall, 2016)
The development of RNA therapeutics required that several major hurdles be overcome, the (1) rapid degradation of exogenous RNA by RNases that are ubiquitous in the environment and tissues; (2) delivery of negatively charged RNA across hydrophobic cytoplasmic membrane; and (3) strong immunogenicity of exogenous RNA that caused cell toxicity and impaired translation into therapeutic proteins
Summary
Tulsi Ram Damase, Roman Sukhovershin, Christian Boada, Francesca Taraballi, Roderic I. RNA therapeutics comprise a rapidly expanding category of drugs that will change the standard of care for many diseases and actualize personalized medicine. These drugs are cost effective, relatively simple to manufacture, and can target previously undruggable pathways. It is a disruptive therapeutic technology, as small biotech startups, as well as academic groups, can rapidly develop new and personalized RNA constructs. In this review we discuss general concepts of different classes of RNAbased therapeutics, including antisense oligonucleotides, aptamers, small interfering RNAs, microRNAs, and messenger RNA.
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