16th Apr 2021
RNA Therapeutics – "Gene"-ius Messengers of Cure
mRNA has become the buzz word amongst scientists, vaccinees & those who are who are waiting in line to get vaccinated. The CDC has published bulletins on the mechanisms & benefits of mRNA vaccines, however, mRNA based therapeutics have remained an area of unquenched curiosity for most of us. Molecular biologists would agree that this is not a new area of research & in fact would celebrate the fact that RNA-based therapeutics are finally seeing the daylight after decades of stay-in-the-dark bench-side development.

On December 18, 2020 U.S. FDA issued an emergency authorization for Moderna’s newly developed messenger-RNA-based vaccine when the entire pharma industry was scrambling to rein-in the COVID-19 pandemic. However, now the potential applications of RNA-based therapeutics look beyond solutions for COVID-19 & some also refer to this as a new era in vaccinology. Scientists are looking to develop personalised cancer vaccines, as well as vaccines for infectious diseases like Zika and Nipah.

As an approach to simplify the complexities of what's been aggrandized as the "central dogma of molecular biology", the figure below provides a brief introduction to the types of RNA & their functions whilst throwing a spotlight on the FDA approved RNA-based drugs. The core modality areas of Moderna's pipeline have also been highlighted & these include several promising focus areas in addition to the COVID-19 vaccine.
  • Vitravene (fomivirsen) was withdrawn from the market, hence excluded from the list of FDA approved drugs
  • Milasen which received approval for one patient has been excluded from the list of FDA approved drugs
  • ASOs (Antisense Oligonucleotides) are short, single stranded DNA/RNA fragments that modulate gene expression
  • RNA Aptamers, also known as "chemical antibodies" are synthetic single stranded DNA/RNA molecules that bind to specific targets
  • Click here for more information on Moderna's pipeline
WHAT'S THE LATEST?
  • Shape Therapeutics has developed RNA editing and tissue-specific AAV delivery technology to debug genetic diseases like Parkinson's
  • Curadigm's proprietary "Nanoprimer Technology" had addressed a key unmet need of RNA-based therapeutics (i.e. treatment efficacy) by significantly increasing the bioavailability and efficacy of siRNA and mRNA in vivo
  • Dicerna has announced new data from preclinical studies of its GalXC-Plus™ RNAi technology which silences disease causing genes in Central Nervous System
  • Now CRISPR technology can be used to target RNA using Cas 13 enzyme! - New York Genome Center
  • Avalon GloboCare has joined the CAR-T bandwagon by developing an RNA-based CAR technology called the "FLASH-CAR" to treat both hematologic & solid malignancies
WHY THE BUZZ?
  • mRNA vaccines developed by Moderna and Pfizer/BioNTech against SARS‐CoV‐2
  • Potential for developing personalized mRNA‐based anti-tumor vaccines
  • The third FDA approval of RNAi-based therapeutic, "Lumasiran" (Oxlumo) for treating a rare genetic disorder in November 2020. Other two approved drugs in the market include Alnylam’s "Patisiran" in 2018 for treating hereditary transthyretin-mediated amyloidosis & Alnylam’s Givlaari (givosiran) for treating acute hepatic porphyria (AHP) in 2019
CHALLENGES?
  • Delivery of intact siRNAs into target cells and tissues without degradation & similar issues with instability (short half-life), tissue selectivity & immunogenicity caused by mRNA drugs
  • Design of delivery methods - currently Cationic Lipid Nanoparticles (LNPs)-based delivery is showing promise, however inefficient transfection and nonspecific targeting challenges pose obstacles
  • Transportation & storage
  • Cost of treatment using RNA-based drugs
WHAT TO WATCH FOR?
  • RNA vaccine candidates developed by Moderna against seasonal flu, HIV, cytomegalovirus and the Nipah virus
  • Inhalable treatment for Cystic Fibrosis by Translate Bio Inc.
  • CureVac's mRNA-based COVID-19 vaccine & other mRNA-based prophylactic vaccines
  • MaxCyte's CARMA™, a novel and proprietary technology for the development of non-viral, human messenger RNA (mRNA)-based, chimeric antigen receptor (CAR) or T-cell receptor (TCR) redirected immune cell therapies.
It's therapeutic
by Meena Ramani