RNA therapeutics have the potential to transform standard patient care and actualize personalized medicine

The rapid development of RNA therapeutics involved several disciplines, including RNA biology, bioinformatics, separation science and nanotechnology. Inputs from these various branches of science helped bypass several impediments, including the potential of rapid degradation of the exogenous RNA drug by ubiquitous RNases, safe delivery of the negatively charged RNA across the hydrophobic cytoplasmic membrane and the potential of cell toxicity and erroneous translation. Several RNA therapeutic drugs have received approval from the U.S. Food and Drug Administration (FDA) or the European Union, while many others are undergoing clinical trials. Antisense RNAs are short oligonucleotides that target complementary sequences in endogenous RNA transcripts to regulate their processing. This category of RNA therapeutics is comprised of antisense oligonucleotides (ASOs), small interfering RNAs and microRNAs. So far, the FDA has approved three ASO drugs, namely nusinersen from Ionis Pharmaceuticals, eteplirsen from Sarepta Therapeutics and inotersen from Ionis Pharmaceuticals and Akcea Therapeutics. These drugs are used to treat spinal muscular atrophy, Duchenne muscular dystrophy and familial amyloid polyneuropathy (FAP), respectively. For instance, a mutation in the transthyretin (TTR) gene leads to FAP owing to the accumulation of aberrant TTR protein in various organs such as kidneys, eyes and nerves. Inotersen, once injected, hybridizes with the endogenous TTR mRNA simulating an RNA/DNA complex and thereby precludes aberrant TTR protein production. Thus, RNA therapeutics can offer major advancements in personalized therapies for myriad patients suffering from genetic disorders. Another interesting category of RNA therapeutics is aptamers, which are single-stranded nucleic acids capable of binding proteins, peptides, carbohydrates and other molecules with high affinity and specificity due to their tertiary structure. Intriguingly, these can perform as agonists, antagonists, bispecific aptamers or carriers of other drugs. Only one aptamer (pegaptanib) has received FDA approval to date. Once injected, mRNAs are translated into peptides or proteins in the cytoplasm to replace defective proteins (produced due to gene mutations) or present antigens for vaccination. Additionally, mRNA drugs can be transfected into cells and used as cell therapy. Another fascinating aspect of RNA therapeutics is that mRNA vaccines can be both prophylactic and therapeutic. Now, there is precedence in science and history about the revolutionary power of mRNA vaccines in alleviating the burden of the COVID-19 pandemic. Of all vaccines under development for COVID-19, the first two to receive FDA approval in December 2020 were RNA vaccines. As compared to conventional vaccines, RNA vaccines have advantages in safety, efficacy, cost-effectiveness, speed and ease of manufacturing. Ultimately, RNA therapeutics has the potential to target all the genes in a cell. RNA therapy also entails fewer issues stemming from stability, delivery and immunogenicity. According to Taraballi and Cooke, “RNA therapeutics is a rapidly emerging field of biotherapeutics. These therapies are based upon a powerful and versatile platform which has nearly unlimited capacity to address unmet clinical needs. RNA therapeutics are destined to change the standard of care for many diseases. The number of RNA drugs under development and in clinical trials is growing rapidly. In addition, hospital-based RNA therapeutics programs will facilitate RNA-based drug development and accelerate translation of transformative therapies from lab bench to patient’s bedside.” RNA therapy holds tremendous potential in altering the future of standard of care. Many novel RNA therapies possibly will emerge that could treat diseases that have no cure to date.