Fostering the Next Generation of Antisense Oligonucleotide Therapies

When the drug fomivirsen was approved by the FDA in 1998 for the treatment of cytomegalovirus retinitis in patients with HIV/AIDs, it was hailed as a milestone in drug discovery because it was the first antisense oligonucleotide (ASO)—a class of drugs that works by targeting RNA to alter gene expression and control aberrant proteins in ways that traditional drugs can’t. An additional nine ASOs have since been approved by the FDA.

Despite the potential ASOs showed in the early days, this class of drugs has faced several hurdles during its development journey. It has taken years for researchers to optimize the compounds and understand the best gene targets and diseases. After fomivirsen was approved, several ASO clinical trials failed due to insufficient efficacy.

I believe conditions are ripe for a resurgence of this important class of drugs. First, technology advances in research and discovery are improving both drug design and target selection. At the same time, the market for ASOs is poised to grow thanks to multiple efforts supporting the development of drugs to treat ultra-rare genetic diseases—an area where ASOs could prove to be ideal first-line treatments.

To look into the future of the ASO class, it’s helpful to first understand its history. The method was first described in the late 1970s by two Harvard scientists who used unmodified DNA ASOs to inhibit viral RNA translation in the Rous sarcoma virus. The following decade brought rapid innovations in antisense methods, including improvements in the stability and binding affinity of ASOs, which in turn improved their potency.

More recently, scientists working in the ASO field discovered certain advantages when targeting RNA species in the cell nucleus. This led to the discovery of novel targets, including long-noncoding-RNAs, which are responsible for regulating gene transcription and post-translational modifications. During the 2010s, several ASO-class therapeutics were approved by the FDA, including nusinersen for spinal muscular atrophy, and eteplirsen and casimersen for Duchenne muscular dystrophy.

Importantly, patents covering some of the key chemical modifications employed to make the most safe and effective ASO compounds expired, encouraging more groups to join the effort to develop antisense therapeutics.

Another factor bolstering the development of ASO therapeutics is the push that’s underway to support the development of new therapies to treat rare diseases. Earlier this year, the FDA’s Center for Biologics Evaluation and Research said it was preparing to pilot test a program aimed at rare diseases that’s modeled after Operation Warp Speed, the government’s effort to accelerate the development of Covid-19 vaccines. The hope is to reduce the time and expense of developing genomic therapies to treat rare diseases. Likewise, the Nucleic Acid Therapy Accelerator, a unit of the Medical Research Council, was established with similar goals in the U.K.

ASOs could be particularly valuable in targeting rare genetic disorders—a fact that’s not lost on one of the pioneers in the field, Dr. Stanley Crooke, who led the development of ASO therapeutics as Ionis Pharmaceuticals’ CEO. In 2020, he founded the nonprofit n-Lorem Foundation, which is on a mission to develop and deliver ASO therapeutics to patients at no cost. Because more ASOs have been administered to humans than any other class of oligonucleotide drug, there is a greater understanding of the safety profile and risks of these medicines. This could make them ideal as first-line therapies for rare genetic disorders, where extensive testing prior to patient administration is not feasible. The N1C is a collaborative formed from several foundations and institutions with the goal of increasing the pace of development of treatments for rare genetic disorders via a variety of new technologies, including antisense, RNA interference, and CRISPR genome editing.

The potential for further growth of ASOs is clear, but hurdles remain. As is the case with all next-generation therapeutics, balancing cellular uptake and potency with minimum off-target effects and toxicity will continue to be a challenge. Researchers working in this field should take advantage of all of the resources available to them—from technology advances to support from regulators and foundations—so they can continue to advance new therapies for patients in need.