Episode 9. Innovation

The inexorable drive for success when most basic needs have been fulfilled propels inventors in amusing places indeed: today, the FAA released its guidance on the use of electrical air taxis - à la Jetsons... 

It takes a special brain to innovate. A precious ability to disregard everything you know, think outside the box, and look at an issue with new eyes. It requires throwing away the existing confines, and re-inventing with a new direction. I can’t do that: I’ve been called “integrating”, “analytical”, and many other things, none of which resemble “innovating”. I construct fantastic objects with Lego blocks, but I would never  have thought of inventing the plastic brick. But I admire the innovators, and help them when my abilities can contribute. Working in a preclinical Contract Research Organization, I assist them all the time: they invent, and IPST characterizes. For 25 years, I’ve “Ooh-ed and Ahhh-ed” as ideas turn to therapies in our labs.

My latest crush: oligonucleotides. These small RNA or DNA segments can inhibit gene translation by binding to the coding RNA (ASOs, miRNAs), or induce silencing complexes to prevent peptide synthesis (siRNAs), or bind to proteins (e.g.: aptamers). In other cases, oligonucleotides guide CRISPR-Cas systems for gene editing by targeting specific DNA sequences for modification or deletion. Just like antibodies, they exhibit wonderful specificity, but whereas antibodies act on peptides, oligonucleotides can modulate gene expression at different levels—transcription, splicing, translation, and even DNA editing.

Current limits pertaining to oligonucleotide delivery to target organs, susceptibility to degradation, and immunogenicity represent challenges well worth tackling for the innovators, given the possibility of treating neurodegenerative diseases like Huntington’s (Stower, 2019) and amyotrophic lateral sclerosis (ALS) Boros, 2022), or Duchenne muscular dystrophy (DMD) (Wilton-Clark, 2023).

In 2024, approximately 20% of the test articles we work with at IPST are oligonucleotides in one form or another, reminiscent of 2014, when approximately 20% of IPST’s work involved therapeutic antibodies. Combined with genetically modified mdx-mice, the antisense oligonucleotides have shown excellent efficiency against DMD, and their tolerability when injected into the spinal cord is very promising for widespread patient treatment.

The specificity and pharmacokinetics of oligonucleotides call for substantial changes in the safety/toxicology testing paradigm: longer safety monitoring, single species toxicology testing… the regulatory paradigm for these small biologics is defining itself (US FDA, 2024), and the preclinical community is paying attention as trailblazers reveal the best development strategies.

Keep and eye out for the latest oligonucleotide-based therapies, and drop us a line if you’re also interested in their development!

References:

Stower, H. Treating Huntington’s with oligonucleotides. Nat Med 25, 877 (2019).

Benjamin D. Boros, et al. Antisense Oligonucleotides for the Study and Treatment of ALS.

Neurotherapeutics, 19: 4, 1145-1158 (2022).

Wilton-Clark H, Yokota T. Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy. Pharmaceutics, 15(3):778 (2023).

US FDA (CDER). Clinical pharmacology considerations for the development of oligonucleotide therapeutics. (2024)