Unlocking Hope: Antisense Oligonucleotides as a Novel Therapeutic Approach for Genetic Diseases

Antisense Oligonucleotides: A Promising New Approach to Treat Diseases

Antisense oligonucleotides (ASOs) are a new class of therapeutic agents that are providing hope for treating a wide range of untreatable and orphan genetic diseases. ASOs work by binding to messenger RNA (mRNA) through complementary base pairing, thereby disrupting protein production from specific genes in a sequence-specific manner. By modulating the expression levels of disease-causing genes, ASOs have the potential to treat the root causes of many disorders. In this article, we discuss the mechanisms, applications and future potential of ASO therapy.

How ASOs Work

The genetic information stored in DNA is transcribed into mRNA, which is then translated into proteins. ASOs work by binding to mRNA through Watson-Crick base pairing. This binding prevents translation and degrades the mRNA, inhibiting production of the target protein. Depending on where they bind on the mRNA, ASOs can work through different mechanisms:

- Steric-blockade ASOs bind to the translation initiation site and prevent ribosomes from attaching, blocking protein synthesis.

- RNase-H-recruiting ASOs recruit the endogenous RNase H enzyme after binding, which degrades the mRNA, thus preventing further protein production.

- Splice-switching ASOs bind to pre-mRNA and alter splicing, either including or excluding exons from the final mRNA. This can correct errors in splicing caused by genetic mutations.

Diseases Treated with ASOs

Several ASO therapies have already been approved or are in clinical trials for rare genetic disorders. Some examples are:

- Spinal muscular atrophy (SMA): Spinraza by Biogen uses splice-switching ASOs to treat SMA by increasing the level of full-length SMN protein. It is the first FDA approved treatment for SMA.

- Duchenne muscular dystrophy (DMD): Exondys 51 by Sarepta and SRP-9001 in clinical trials use splice-switching ASOs to skip mutations in the DMD gene and restore the reading frame.

- Huntington's disease: IONIS-HTTRx in clinical trials aims to lower levels of the mutated huntingtin protein through an RNase H ASO.

- ATTR amyloidosis: Onpattro by Alnylam was the first RNAi drug approved for use in humans to treat the disease. It employs steric-blockade GalNac-conjugated ASOs.

- Familial chylomicronemia syndrome: Waylivra by Ionis targets production of apolipoprotein C-III using RNase H ASOs.

Beyond Genetic Disorders

Research into ASO applications is rapidly expanding beyond monogenic disorders. Some areas showing promise include:

Inflammation: Several ASOs targeting proteins involved in inflammation like TNF-alpha, IL-1beta and complement component C5 are in clinical trials for treating inflammatory conditions like atherosclerosis, lupus, and rheumatoid arthritis.

Cancers: ASOs are being tested preclinically and clinically to target oncogenes, tumor suppressors, proteins involved in DNA repair, cell cycle regulation and metastasis for treating various cancers.

Infectious diseases: ASOs targeting host factors involved in viral replication and also directly targeting viral RNA are under investigation for treating hepatitis B, Zika virus, HIV and various other viral infections.

Neurodegenerative diseases: In addition to Huntington's disease trials, ASOs targeting alpha-synuclein, tau and other proteins are showing preclinical promise for Parkinson's, Alzheimer's and related diseases.

Future Prospects

The successes of approved ASO therapies have reignited the oligonucleotide field with billions in investments pouring into research. Advancements in oligonucleotide chemistry, conjugation strategies, targeted delivery and manufacturing are helping ASOs overcome hurdles to treatment of more common diseases. Further development of multi-target "cocktail" approaches and combinatorial therapies are expanding the toolbox. If the ongoing pace of research continues, ASOs hold immense promise to serve as a new class of therapies for a large number of currently untreatable medical conditions in the years to come.

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