Антисенс терапиясы: Женетикалық ауруларға және басқа сырқаттарға емдеу жолы

Form of treatment for genetic disorders and other illnesses

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

The common stem for antisense oligonucleotides drugs is rsen. The substem virsen designates antiviral antisense oligonucleotides.

ASO based drugs employ highly modified, single stranded chains of synthetic nucleic acids that achieve wide tissue distribution with very long half lives. For instance, many ASO based drugs contain phosphorothioate substitutions and 2' sugar modifications to inhibit nuclease degradation enabling vehicle free delivery to cells.

Phosphorothioate ASOs can be delivered to cells without the need of a delivery vehicle. ASOs do not penetrate the blood brain barrier when delivered systemically but they can distribute across the neuraxis if injected in the cerebrospinal fluid typically by intrathecal administration. Newer formulations using conjugated ligands greatly enhances delivery efficiency and cell type specific targeting. It was developed by Biogen under a licensing agreement with Ionis Pharmaceuticals. In trials the drug was found to lower levels of an ALS biomarker, neurofilament light change, and in long term trial extensions to slow disease.

Milasen is a novel individualized therapeutic agent that was designed and approved by the FDA for the treatment of Batten disease. This therapy serves as an example of personalized medicine. In 2019, a report was published detailing the development of milasen, an antisense oligonucleotide drug for Batten disease, under an expanded access investigational clinical protocol authorized by the Food and Drug Administration (FDA).

Fomivirsen (marketed as Vitravene), was approved by the U. S. FDA in August 1998, as a treatment for cytomegalovirus retinitis.

Several morpholino oligos have been approved to treat specific groups of mutations causing Duchenne muscular dystrophy. In September 2016, eteplirsen (ExonDys51) received FDA approval for the treatment of cases that can benefit from skipping exon 51 of the dystrophin transcript. In December 2019, golodirsen (Vyondys 53) received FDA approval for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript. In August 2020, viltolarsen (Viltepso) received FDA approval for the treatment of cases that can benefit from skipping exon 53 of the dystrophin transcript.

Volanesorsen was approved by the European Medicines Agency (EMA) for the treatment of familial chylomicronaemia syndrome in May 2019.

In January 2013 mipomersen (marketed as Kynamro) was approved by the FDA for the treatment of homozygous familial hypercholesterolemia.

Inotersen received FDA approval for the treatment of hereditary transthyretin mediated amyloidosis in October 2018. 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. and soon after, from other regulatory agencies worldwide.

As of 2020 more than 50 antisense oligonucleotides were in clinical trials, including over 25 in advanced clinical trials (phase II or III).

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.

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.

Several ASOs are currently being investigated in disease models for Alexander disease, ATXN2 (gene) and FUS (gene) amyotrophic lateral sclerosis, Angelman syndrome, Lafora disease, lymphoma, multiple myeloma, myotonic dystrophy, Parkinson's disease, Pelizaeus–Merzbacher disease, and prion disease, Rett syndrome, spinocerebellar Ataxia Type 3.