Avidity Biosciences has a pipeline of AOC therapeutics focused on neuromuscular diseases. Their leading candidate, AOC 1001, is a siRNA conjugated with a monoclonal antibody (mAb). 207 AOC 1001 has an ongoing phase I/II trial in adults with myotonic dystrophy type 1 (DM1). DM1 is a progressive neuromuscular disease that impacts skeletal and cardiac muscle. DM1 is caused by an abnormal number of CUG triplet repeats in the myotonic dystrophy protein kinase gene (DMPK), reducing muscle blind-like protein (MBNL) activity and disrupting muscle development. AOC 1001 is designed to reduce DMPK levels and CUG triplet repeats so that MBNL can perform normally. Avidity Biosciences has also developed an AOC to treat DMD. The oligonucleotides are designed to promote skipping of specific exons to produce dystrophin in patients with DMD. Their leading DMD drug candidate, AOC 1044, can induce exon skipping specifically for exon 44, and clinical trials are planned for 2022. 207 Eye diseases including visual impairment affect 2.2 billion people globally. Macular degeneration, which causes loss in the center of the field of vision and is irreversible, affects 196 million people. Macugen, developed by Gilead Sciences, was the first FDA-approved (2014) RNA aptamer treatment for neovascular age-related macular degeneration. Macugen targets the VEGF protein in the eye, reducing the growth of blood vessels to control the leakage and swelling that cause vision loss. As age-related macular degeneration progresses, geographic atrophy (GA), a chronic progressive degeneration of the macula, can develop. Zimura by Iver Bio is another RNA aptamer therapeutic and is currently in a phase III clinical trial. Zimura inhibits complement C5 217 , which is involved in the development and progression of AMD. In clinical trials, Zimura slowed the progression of GA over 12 months in individuals with age-related macular degeneration. 216 QR-504a from ProQR Therapeutics is an investigational RNA ASO therapeutic that is in ongoing phase I/II clinical trials. 218 QR-504a is designed to slow vision loss in individuals with Fuchs endothelial corneal dystrophy (FECD) which results from trinucleotide repeat expansion mutations in the TCF4 gene. 219 Kidney disease affects over 850 million people worldwide. Primary hyperoxaluria type 1 (PH1) is a genetic kidney disease characterized by the overproduction of oxalate, which leads to kidney stones, kidney failure, and systemic oxalosis. The siRNA therapeutic Oxlumo was developed by Alynlam and approved by the FDA in 2020. Oxlumo targets the hydroxy acid oxidase 1 gene (HAO1), which encodes glycolate oxidase. Oxlumo reduced urinary oxalate excretion in patients with progressive kidney failure in PH1. The majority of patients had normal or near-normal levels of oxalate after 6 months of treatment. Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the PKD1 or PKD2 gene. It is characterized by cysts within the kidneys, often leading to kidney failure. To treat ADPKD, Regulus designed RGLS4326, a second-generation oligonucleotide that inhibits miR-17, which produces kidney cysts. RGLS4326 binds to miR-17 microRNAs, inhibits miR-17 activity, and reduces disease progression. IgA nephropathy is a chronic kidney disease that is caused by deposits of protein immunoglobulin A (IgA) inside the glomeruli of the kidneys. Overproduction of complement factor B (FB) is associated with increased IgA nephropathy. Ionis has partnered with Roche to develop a ligand-conjugated ASO therapeutic, IONIS-FB-LRx, which targets FB to reduce the production of IgA and alleviate the symptoms of IgA nephropathy. 154 Respiratory diseases affect more than 1 billion people worldwide. 229 COVID-19 brought acute respiratory distress syndrome (ARDS) to the forefront of medical news during the pandemic. ARDS is a severe inflammatory lung disease with a mortality rate of over 40%. Inflammation leads to lung tissue injury and leakage of blood and plasma into air spaces, resulting in low oxygen levels and often requiring mechanical ventilation. 230 Descartes-30 is an engineered mRNA cell therapy product by Cartesian Therapeutics. It comprises human mesenchymal stem cells that secret two human DNases for degrading ARDS-causing neutrophil extracellular traps (NETS). 178 . Descartes-30 is currently in phase I/II clinical trials. Cystic fibrosis is caused by a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) protein, resulting from mutations in the CFTR gene. Without CFTR, mucus in various organs including the lungs is extremely thick and sticky. MRT5005, developed by Translate Bio, is an mRNA therapeutic that bypasses this mutation by delivering mRNA encoding a fully functional CFTR protein to the cells in the lungs through nebulization. Although initial interim results from clinical studies showed promise, 234 results from the second interim phase I/II clinical trial showed no increase in the lung function of individuals receiving MRT5005. The siRNA therapeutic ARO-ENaC is designed by Arrowhead Pharmaceuticals to reduce epithelial sodium channel alpha subunit (αENaC) in the lungs and airways. Increased ENaC contributes to airway dehydration and increased mucus. However, Arrowhead paused a phase I/II study of ARO-ENaC in July 2021 after safety studies showed local lung inflammation in rats. 237 Blood diseases affect one or more components of blood. Sickle cell disease is a type of blood disease that causes red blood cells to become misshapen and break down. Beta-thalassemia syndromes are a group of blood diseases that result in reduced levels of hemoglobin in red blood cells. 241 BEAM-101, Beam Therapeutics leading ex vivo base editor, is a patient-specific, autologous hematopoietic investigational cell therapy. BEAM-101 introduces base edits that mimic the single nucleotide polymorphisms found in individuals with hereditary persistence of fetal hemoglobin (HPFH), which could alleviate the effects of mutations causing sickle cell disease or beta-thalassemia since the fetal hemoglobin doesn't become misshapen. 242 Beam plans to initiate a phase I/II clinical trial to assess the safety and efficacy of BEAM-101 for the treatment of sickle cell disease. 242 BEAM-101 uses an electroporation delivery system. Silence Therapeutics has RNA therapeutics for blood diseases such as thalassemia, myelodysplastic syndrome, and rare iron-loading anemias. Their siRNA therapeutic SLN124 targets TMPRSS6, a gene that prevents the liver from producing hepcidin. Phase I clinical trial data showed that SLN124 improved red blood cell production and reduced anemia by increasing the levels of hepcidin. Keloid scarring is a type of pathological condition that forms abnormally thick scarring after a skin injury. STP705, from Sirnaomics, is a siRNA therapeutic in phase II clinical trial for the treatment of keloid scars. 246 STP705 targets both TGF-β1 and COX-2 gene expression with polypeptide nanoparticleenhanced delivery. The synergistic effect of simultaneous silencing TGF-β1 and COX-2 may reverse skin fibrotic scarring by decreasing inflammation and activating fibroblast apoptosis. This mechanism of action of STP705 can be widely applied for the treatment of other fibrotic conditions. Autoimmune diseases are characterized by immune activation in response to normal antigens. 248 mRNA-6231 from Moderna is an mRNA encoding IL-2 mutein that activates and expands the regulatory T cell population and dampens self-reactive lymphocytes. Alcohol use disorder (AUD) is the inability to control alcohol use despite adverse social, occupational, or health consequences. According to the World Health Organization, AUD affects over 283 million people globally. Alcohol is metabolized in the liver to acetaldehyde via alcohol dehydrogenase and then to acetic acid by aldehyde dehydrogenase 2 (ALDH2). Inhibiting ALDH2 results in unpleasant symptoms due to the increased acetaldehyde when alcohol is not fully metabolized. The siRNA therapeutic DCR-AUD by Dicerna knocks down ALDH2 protein expression in the liver, which results in increased acetaldehyde levels that discourage continued alcohol use in AUD patients. 252 RNA is composed of nucleosides that consist of a nucleic acid base attached to a D-ribose through a -N-glycosyl bond between the ribose and the pyrimidine bases (uracil and cytosine) or the purine bases (adenosine and guanosine). The nucleosides are connected by a phosphodiester bond using the phosphate between the 3' and 5' carbons on adjacent ribose molecules (Figure ). RNAs can be modified on the nucleic acid base and on the phosphate and the ribose of the sugar-phosphate backbone, as shown illustrated Figure with color circles. Figure . An example of RNA structure and modification sites. Green circles, modification sites on the phosphate; red circles, attachment sites for modifications on the ribose; blue circles, attachment sites for modifications on the nucleic acid base: 1-methylpseudouridine (1meΨ), cytosine (C), uridine (U), guanosine (G), and adenosine (A).