Antisense therapy

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.

Developments in ASO modification are separated into three generations. Generation one is called backbone-modified and focuses on the phosphodiester group of the nucleotide. This impacts inter-nucleotide binding. These modifications led to better distribution, reduced urinary excretion, and prolonged residence time of the ASOs in the cell. Some examples of first generation modifications include the addition of a phosphorothioate group (PS), methyl group, or nitrogen. The most common is the phosphorothioate group (PS) in which the oxygen atoms of a phosphodiester group are replaced with sulfur atoms, greatly improving efficacy and reducing degradation. Generation two is sugar-modified, focused on the ribose sugar of the nucleotide. This generation saw improved binding affinity while reducing degradation. Some examples of generation two modifications are the substitution of R group with morpholine group (MO) and the usage of phosphorodiamidate morpholino oligomer (PMO) and thiomorpholine oligomer (TMO) as linkages between the ribose sugar and phosphodiester group in the backbone. Generation three is nucleobase-modified, the least common type of modification. These modifications enhanced binding affinity and cell penetration while reducing degradation and off-target effects. Examples include the introduction of G-clamps, pseudoisocytosine, and the substitution of bases with amine, thione, halogen, alkyl, alkenyl, or alkynyl groups.

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.

Tofersen (marketed as Qalsody) was approved by the FDA for the treatment of SOD1- associated amyotrophic lateral sclerosis (ALS) in 2023. 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. Under the terms of the FDA's accelerated approval program, a confirmatory study will be conducted in presymptomatic gene carriers to provide additional evidence.

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). Milasen "itself remains an investigational drug, and it is not suited for the treatment of other patients with Batten's disease" because it was customized for a single patient's specific mutation. However it is an example of individualized genomic medicine therapeutical intervention.