exon 53 of the dystrophin transcript. Familial chylomicronaemia syndrome Volanesorsen was approved by the European Medicines Agency (EMA) for the treatment of familial chylomicronaemia syndrome in May 2019. Familial hypercholesterolemia In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia. Hereditary transthyretin-mediated amyloidosis Inotersen received FDA approval for the treatment of hereditary transthyretin-mediated amyloidosis in October 2018. The application for inotersen was granted orphan drug designation. It was developed by Ionis Pharmaceuticals and licensed to Akcea Therapeutics. Patisiran (sold under Onpattro) was developed by Alnylam Pharmaceuticals, and also approved for use in the US and EU in 2018 with orphan drug designation. Its mechanism-of-action is the active substance of small interfering RNA (siRNA), which allows it to interfere with and block the production of trasnthyretin. As such, it was the first FDA-approved siRNA therapeutic. Spinal muscular atrophy In 2004, development of an antisense therapy for spinal muscular atrophy began. Over the following years, an antisense oligonucleotide later named nusinersen was developed by Ionis Pharmaceuticals under a licensing agreement with Biogen. In December 2016, nusinersen received regulatory approval from FDA and soon after, from other regulatory agencies worldwide. Investigational therapies Current clinical trials As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in advanced clinical trials (phase II or III). Phase III trials Amyotrophic lateral sclerosis Tofersen (also known as IONIS-SOD1Rx and BIIB067) is currently being tested in a phase 3 trial for amyotrophic lateral sclerosis (ALS) due to mutations in the SOD1 gene. Results from a phase 1/2 trial have been promising. It is being developed by Biogen under a licensing agreement with Ionis Pharmaceuticals. Hereditary transthyretin-mediated amyloidosis A follow-on drug to Inotersen is being developed by Ionis Pharmaceuticals and under license to Akcea Therapeutics for hereditary transthyretin-mediated amyloidosis. In this formulation the ASO is conjugated to N-Acetylgalactosamine enabling hepatocyte-specific delivery, greatly reducing dose requirements and side effect profile while increasing the level of transthyretin reduction in patients. Huntington's disease Tominersen (also known as IONIS-HTTRx and RG6042) was tested in a phase 3 trial for Huntington's disease although this trial was discontinued on March 21, 2021, due to lack of efficacy. It is currently licensed to Roche by Ionis Pharmaceuticals. Phase I and II trials Clinical trials are ongoing for several diseases and conditions including: Acromegaly, age related macular degeneration, Alzheimer's disease, amyotrophic lateral sclerosis,