The human genome contains around 20,000 protein coding genes, each a template for a protein that plays a role in the body’s structure, function and regulation. [1, 2] A small percentage of gene variants, whether hereditary or non-inherited, trigger the production of disease-causing faulty proteins, leading to disease. [3]
Diseases caused by changes in proteins range from mild to severe, and include rare diseases, cardiovascular disease, cancer and other disorders. Treatment approaches for genetic diseases have focused on managing symptoms through small molecule and biologic therapeutics. Newer approaches target the genetic mutations themselves, by replacing (gene therapy), removing (gene editing) or muting (gene silencing) the genetic code. [4] These target the molecular causes of disease, rather than just treating the symptoms.
Making sense of antisense
The gene silencing approach works by targeting mutations and preventing or reducing expression of disease-causing proteins, and the naturally occurring mechanisms include antisense oligonucleotides (ASOs) and RNA interference (RNAi) strategies. [5, 6]
ASOs are stabilised single- or double-stranded synthetic oligonucleotides that bind to the target DNA, triggering the cleaving of the target mRNA (messenger RNA) by RNase. In the RNAi process, after administration, small interfering ribonucleic acids (siRNAs) and microRNAs (miRNAs) bind to the mRNA, either inhibiting the translation of the mRNA into protein, or inducing its degradation. [5, 6] With both approaches, each oligonucleotide is specific to a single mutation, but mixtures could be used to treat a disorder associated with a number of genetic variants.
Fomivirsen (Vitravene) was the first ASO to be approved by the US Food and Drugs Administration (FDA), in 1998. It was developed by Isis Pharmaceuticals and licensed to Novartis for the treatment of cytomegalovirus (CMV) retinitis in people who were HIV-positive. The drug was withdrawn in 2001 as the success of antiretroviral therapy reduced demand. It however provided proof-of-concept for antisense oligonucleotides, with the next drug, Ionis/Genzyme’s mipomersen (Kynamro), being approved in 2013 for the treatment of homozygous familial hypercholesterolemia. [7, 8]
As of March 2024, the FDA and European Medicines Agency (EMA) had approved 12 antisense oligonucleotides and six siRNAs. [9] The global market for antisense oligonucleotides and RNAi was worth around $4.4 billion in 2023 and is expected to grow at 18.2% CAGR to reach $19.7 billion in 2023. This is driven by the increasing prevalence of neurodegenerative and genetic disorders, growing investments in research related to gene expression and delivery technologies, and the growth in regulatory approvals for antisense therapeutics as the key drivers behind this growth. [10]
Research into ASOs is thriving, particularly in genetic disorders, neurological diseases, and cancer. As an example, SynaptixBio is developing an ASO to treat H-ABC, the most severe form of the rare disease TUBB4A leukodystrophy. This genetic neurodegenerative disorder affects around 1600 babies and children worldwide every year and makes up around 9% of all leukodystrophies. The gain of function mutation in the TUBB4A gene leads to a failure to lay down myelin around the nerves, resulting in seizures, muscle contractions, uncontrollable limb movements and issues with speech. Life expectancy depends on severity of the disease and many die by their late teens. [11]
SynaptixBio’s H-ABC ASO, SB-19642, is a DNA molecule with RNA ‘wings’ that binds to the mRNA. It is highly specific, targeting only the aberrant tubulin, allowing the other tubulins to continue to play their physiological roles. The company is currently selecting a candidate ASO to begin Phase I clinical trials. [12]
Biogen’s ASO BIIB080, the first gene silencing approach to Alzheimer’s disease, has been assessed in a UK Phase II trial. The ASO targets the Tau protein gene, one of two proteins known to be prevalent in patients with Alzheimer's disease. The trials have recently bee...
(All Rights Reserved)