The Future of Nucleic Acid Therapies
Medicines derived from genetic building blocks have the potential to transform patient care
Brian Carothers | | Opinion
In diseases that arise from genetic mutations, most therapies address the abnormal protein that results. But not nucleic acid therapies; these revolutionary treatments target the biological pathway behind the proteins. Consider, for example, a drug that targets the mRNA upstream of protein expression, thereby affecting protein synthesis – and disease progression.
In short, nucleic acid therapies can alter protein manufacturing throughout the body – a powerful tool for fighting disease. These relatively new treatments show promising results in both the clinic and commercial markets. Market growth is extremely strong, with increasing investments in research, development, and clinical programs. Coupled with the recent uptick in regulatory approvals, the future looks bright.
These treatments are highly flexible – they not only act as gene replacements, but can also be used for immunization (with clinical trials ongoing for nucleic acid-based vaccines). What’s more, their success story actually goes further back than many people may realize. The first DNA-based therapy (formivirsen, a treatment for immunocompromised patients with cytomegalovirus retinitis) was first approved in 1998. RNA therapy is a more recent development, with the first of these (patisiran, approved for polyneuropathy caused by hereditary transthyretin-mediated amyloidosis) approved in 2018. And, though patisiran is an RNA interference therapy, other types of noncoding RNA and microRNAs are also under intense investigation as disease treatments.
The synthetic manufacturing process for nucleic acid drugs is both complex and critical for success. Understanding the nucleic acid drugs’ sequence, (im)purity profile, and overall material quality requires a skilled workforce wielding state-of-the-art high-performance LC and MS instruments.
Innovators in the CRISPR gene editing area are using programmed nucleic acid synthesis to produce single guide RNA (sgRNA) at chain lengths of 100 nucleotides. As a result, the diversity of structures to examine – not to mention their complexity – is rapidly increasing. This requires expanded analytical capability. Verifying the structures’ sequence content and base order is particularly challenging because it involves degrading the oligonucleotide either chemically or ionically. We tend to use the ionic energy of a mass spectrometer coupled with informatics software in which the fragment data from MS/MS is compared with the theoretical oligonucleotide fragment pattern. This approach can achieve up to 100 percent quality verification for batch analysis of nucleic acid drugs.
Combining techniques like chromatography and MS is crucial for the delivery of quality product – not least in our own Nucleic Acid Solutions Division. The division is a contract development and manufacturing organization that aims to provide our clients with effective drug substance to treat patients with unmet medical needs, building on our 25 years of experience in providing microarray services for nucleic acid analysis.
The use of nucleic acids for therapy is a “fairly young” technology whose applications could stretch far beyond those currently considered – typically rare and orphan diseases. Take the case of COVID-19, for example. We could combat the virus in many different ways using nucleic acids, whether through RNA interference (RNAi) therapies that disrupt protein metabolism or as an adjuvant to support a vaccine. I am confident that, in the future, nucleic acid-based therapies will be well-established and broadly used in medicine to address population-level challenges – and I am extremely excited to be a part of this ever-expanding field.
Supporting Information for this article was provided by Blake Unterreiner, Director of Business Development and Customer Relations, and Joe Guiles, PhD Director, Product Development.