RNA Therapeutics

RNA RNA RNA therapeutics are a class of biopharmaceuticals that use RNA to treat or prevent human diseases, including infectious diseases, genetic conditions and cancer. This field of medicine is rapidly evolving and offers new avenues for targeting “the undruggable”. In this infographic, we’ll explore why. Let’s start by asking – what is RNA? RNA ribo ac { nucleic id } A biological molecule that is similar to DNA, but has only one helical strand of ribonucleotide bases: DNA, trapped in a cell’s nucleus, is transcribed to RNA that can then be translated to produce proteins within the cytoplasm. Proteins are the Adenine (A) functional workhorses of the cell, conducting a myriad of important biological processes. Guanine (G) DNA to RNA Cytosine (C) nd export to cytoplasm and export to cytoplasm RNA in cytoplasm Uracil (U) Protein translation from mRNA at DNA in nucleus at Protein Several key discoveries in RNA biology have paved the way for RNA therapeutics: 1956 1962 1977 1998 Rich and Davies RNA replicase RNA splicing Discovery of RNA demonstrate that two is discovered. is discovered. interference. RNAs can form base pairs with one another. 1961 1970 1993 Messenger RNA Reverse transcriptase (mRNA) is discovered. is discovered. Discovery of microRNA. RNA is a key player in the central dogma of molecular biology. Considering that many human diseases are caused by errors in this dogma, we can start to appreciate how useful RNA can be as a therapeutic modality. RNA therapeutics are likely to change the standard of care for many diseases. Targeting the undruggable Only 0.05% of the human genome has been drugged by small molecule drugs and Fast development antibodies, as most of the genome does not RNA therapeutics can be designed and encode protein. Some RNA molecules can developed much faster than traditional target mRNAs and noncoding RNAs directly, small drugs or gene therapies. The design meaning that RNA can hypothetically target and synthesis of RNA molecules is also more any gene of interest, even if it does not adaptable, a critical feature for responding encode a protein. to public health emergencies. Stimulating the Short half-life immune system HL Some RNA molecules, like mRNA, have RNA can be used to effectively stimulate a short half-life. This can be beneficial the immune system, creating new as it enables a controlled and reversible opportunities for vaccine development. therapeutic effect. The BNT162b2 COVID-19 vaccine was the first mRNA-based vaccine to be approved for human use in history. Low risk of mutagenesis Unlike gene therapies, RNA therapeutics Personalized medicine do not integrate into the genome, and do not cause unintended mutations. RNA therapeutics can be customized for individual patients. The different types of RNA Scientists have discovered a variety of RNA molecules that have diverse roles, and many are still yet to be determined. RNA molecules can be used to modulate gene expression in various ways, such as by expressing therapeutic proteins, targeting RNA molecules to alter their function or silencing specific genes, for example. Examples of RNA therapeutics 1 RNA aptamers RNA aptamer Pegaptanib was the first RNA therapeutic approved by the US Food and Drug Administration (FDA) for the treatment of age-related macular degeneration (AMD). Pegaptanib interacts with vascular endothelial growth factor (VEGF), stopping it from interacting with its receptors. Protein function is blocked 2 Antisense oligonucleotides (ASOs) Anti-sense RNA to target RNA and modulating gene expression either by: • inhibiting translation • promoting RNA degradation • or altering splicing. mRNA therapies work by introducing synthetic mRNA molecules into cells, which instruct the cell to produce a specific protein. This protein could be used to treat a disease or to trigger an immune response. mRNA is being used to create flu, RSV and HIV vaccines, and therapies to treat conditions such as type I glycogen storage disease. Nusinersen was approved by the US FDA in 2016 to treat spinal muscular atrophy (SMA), a genetic neuromuscular condition. It corrects splicing errors in the SMN2 gene, increasing production of the functional SMN protein and improving motor function. 1 3 2 to target RNA and modulating gene • inhibiting translation • promoting RNA degradation • or altering splicing. mRNA therapies work by introducing synthetic mRNA molecules into cells, which instruct the cell to produce a specific protein. This protein could be used to treat a disease or to trigger an immune response. mRNA is being used to create flu, RSV and HIV vaccines, and therapies to treat conditions such as type I glycogen storage disease. Nusinersen was approved by the US FDA in 2016 to treat spinal muscular atrophy (SMA), a genetic neuromuscular condition. It corrects splicing errors in the SMN2 gene, increasing production of the functional SMN protein and improving motor function. 1 3 2 • inhibiting translation • promoting RNA degradation Anti-sense RNA complexed with pre-mRNA or mature mRNA • or altering splicing. Nusinersen was approved by the US FDA in 2016 Spliced mRNA to treat spinal muscular atrophy (SMA), a genetic neuromuscular condition. Modulation of splicing Degradation of pre-mRNA of mature RNA It corrects splicing errors in the gene, SMN2 increasing production of the functional SMN protein and improving motor function. 3 Double stranded RNA RNA interference (RNAi) Dicer Small interfering RNA Use small RNA molecules to silence target genes, halting the prevention of proteins RISC by interfering with mRNA. siRNA and The two main forms of RNAi are genome mRNA complex derived microRNAs (miRNAs) and small interfering RNAs (siRNAs). Currently four siRNA therapeutics are approved by the FDA. mRNA degradation 4 mRNA C AAA (including mRNA vaccines, therapeutics and cell therapies) Mature mRNA • Introduced into cell mRNA molecules into cells, which instruct the cell to produce a specific protein. This protein could be used to treat a disease or to trigger an immune response. mRNA is being used to create flu, RSV and HIV vaccines, and therapies to treat conditions such as type I glycogen storage disease. Nusinersen was approved by the US FDA in 2016 to treat spinal muscular atrophy (SMA), a genetic neuromuscular condition. It corrects splicing errors in the SMN2 gene, increasing production of the functional SMN protein and improving motor function. 1 3 2 4 • Undergoes translation cell to produce a specific protein. This protein could be used to treat a disease or to trigger an immune response. mRNA is being used to create flu, RSV and HIV vaccines, and therapies to treat conditions such as type I glycogen storage disease. Nusinersen was approved by the US FDA in 2016 to treat spinal muscular atrophy (SMA), a genetic neuromuscular condition. It corrects splicing errors in the SMN2 gene, increasing production of the functional SMN protein and improving motor function. 1 3 2 4 cell to produce a specific protein. This protein could be used to treat a disease or to trigger an immune response. mRNA is being used to create flu, RSV and HIV vaccines, and therapies to treat conditions such as Functional enzyme or antigen is produced type I glycogen storage disease. To date, the development of RNA therapies has focused largely on ASOs, RNAis and mRNA-based drugs or vaccines. RNA theraputic type 118 150 Summary of RNA therapeutic 100 Number 54 ongoing clinical 44 of trial landscape. trials 50 6 Adapted from Curreri et al. 0 mRNA siRNA ASO Other Manufacturing RNA therapies Different methods and bioprocessing workflows are used to design and develop RNA therapeutics. Here’s a “classic” example of a manufacturing process. 1 Once a workflow has been established, production facilities can typically “switch gears” quickly and adapt this workflow to produce Obtain RNA sequence(s) other types of RNA drugs. for desired indication. Often gathered from a digital bank. 2 3 4 5 DNA template production Drug substance Drug product Fill and finis manufacturing formulation • Clone • Purificatio • Cell -free transcription • Self -assebly of RNA • Expand • Sterilization of mRNA lipid nanoparticles • Linearize • Packaging 7 6 Subject to regulatory Clinical trials to test approval, global efficacy and safety production and distribution of the product. may be the next step. Despite many RNA therapeutics entering clinical trials, only a few have received FDA approval. RNA therapies – the present and the future Challenges associated with RNA-based therapeutics include: Instability Making sure RNA molecules are stable and developing effective delivery methods to target specific cells Delivery without degradation is a challenge. Addressing the potential of RNA molecules to activate the immune system, Demonstrating safety Immunogenicity which can lead to adverse and efficacy and gaining reactions or reduced regulatory approval therapeutic efficacy for RNA therapies can be a long and Clinical validation expensive process. The swift expansion of RNA therapeutics can be attributed to the resolution of some of these challenges. Room for improvement remains, however the global RNA therapy clinical trials market is expected to reach $3.5 billion by 2030. Sponsored by