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  • Writer's pictureSociety of Bioethics and Medicine

Oligonucleotides: Medical Advancements Met with Manufacturing Concerns

Written by Shane McGlone

Edited by Rayyan Bhuiyan

A feature released by Nature Medicine in 2019 titled “Looking forward 25 years: the future of medicine” overviews the thoughts and opinions of the current biomedical community. To experts in the field, researchers primed the following question: “What will shape the next 25 years of medical research?” [1] Their unanimous answer: gene therapy.


Gene therapy is described by the National Institutes of Health as, “the treatment of disease by transfer of genetic material into cells.” [2] According to the central dogma of cell biology, DNA produces RNA which directs protein formation. Diseases in our body are traced to dysfunction within the macromolecules that direct, support, and provide for our cells. Utilizing gene therapy can specifically target the precursors to malfunctioning proteins, or enable the body to produce more of a protein that fights disease. While disease treatment has historically centered around treating general biomarkers of disease, the complex origins of health issues would respond better to a more precise model. The main benefit of gene therapy is that it is incredibly specific: allowing medicine to be intimately personalized to the patient and their condition. [3]


However, the science is very new and has many limitations. With such a new technology, it is hard to assess long term effects of its therapeutic usage. Clinical trials are often challenging to see through, though the FDA does currently approve around 30 gene therapies. [4] As drugs are approved, however, new challenges continuously arise: particularly in manufacturing.


Such is the case with oligonucleotides: small single or double-stranded nucleotide polymers capable of modulating gene expression via DNA or RNA binding. The coding sequence of oligonucleotides complement those of our bodies’ genetic sequence, allowing for segments of concern to be targeted. [5] These tiny genetic sequences are proving to be very useful in the treatment of rare diseases such as cytomegalovirus, homozygous familial hypercholesterolemia, and many cancers. [6] Biotech companies are rushing to patent oligonucleotide therapies, with 130 clinical trials currently underway. However, manufacturing challenges such as product loss are hindering the progress of these promising therapies.


A recent article released from Science on April 14, 2024, highlights this production issue in the advancement of oligonucleotide therapy. While biomedicine has made many advancements, biochemical engineers are being called upon to bridge the gap where production falls short. The process of isolating and purifying synthesized oligonucleotides is currently unsustainable. The modern filtration systems utilized in larger biomolecule exclusion are proving to fall short for the new gene therapy. In the present model, manufacturing the nucleotides causes large product loss and is significantly lacking in cost-efficiency.


The main issue is that oligonucleotide synthesis relies upon phosphoramidite chemistry: a process in which nucleotide sequences are lengthened via deprotection and oxidation mechanisms. The process utilizes smaller column sizes than other purification methods, which slows down production at the cost of increased product purity. Per batch, less than 10 kg of oligonucleotide molecules are formed representing only a 50% yield.


Secondly, the washing process requires a significant amount of acetonitrile to remove impurities (around 1000 kg per kg of formed product). This is both costly and damaging to the environment, as large amounts of chemical waste unnecessarily deplete resources. Looking forward, science calls upon the invention of new purification techniques to eliminate waste and boost yield. Though the current product is 90% pure, this number can also be optimized (especially at a lower ratio to the yield). [7]


The story of oligonucleotides, though revealing of halts in progress, is truly promising for the future of medicine. In only 20 years, dozens of drugs have entered the market, despite market challenges. While manufacturing capabilities present a large obstacle to the sustainable future of gene therapy, the result has shown that science strives for collaboration. As engineers, chemists, biologists, and environmental scientists come together to assess the problem, we are reminded of the efforts, which combine to raise us further into the future of medicine and humanity.


References:

[1] Atkins, Carl D., et al. “Looking Forward 25 Years: The Future of Medicine.” Nature Medicine, vol. 25, no. 12, Dec. 2019, pp. 1804–07. https://doi.org/10.1038/s41591-019-0693-y.


[2] Scheller, E L, and P H Krebsbach. “Gene therapy: design and prospects for craniofacial regeneration.” Journal of dental research vol. 88,7 (2009): 585-96. doi:10.1177/0022034509337480


[3] Professional, Cleveland Clinic Medical. “Gene Therapy.” Cleveland Clinic, my.clevelandclinic.org/health/treatments/17984-gene-therapy.


[4] Research, Center for Biologics Evaluation And. “Approved Cellular and Gene Therapy Products.” U.S. Food And Drug Administration, 18 Mar. 2024, www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.


[5] Moumné, Lara et al. “Oligonucleotide Therapeutics: From Discovery and Development to Patentability.” Pharmaceutics vol. 14,2 260. 22 Jan. 2022, doi:10.3390/pharmaceutics14020260


[6] Roberts, Thomas C., et al. “Advances in Oligonucleotide Drug Delivery.” Nature Reviews. Drug Discover/Nature Reviews. Drug Discovery, vol. 19, no. 10, Aug. 2020, pp. 673–94. https://doi.org/10.1038/s41573-020-0075-7.


[7] Obexer, Richard, et al. “Modern Approaches to Therapeutic Oligonucleotide Manufacturing.” Science, vol. 384, no. 6692, Apr. 2024, https://doi.org/10.1126/science.adl4015.

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