Demaris Mills is president at Integrated DNA Technologies, a global genomics solutions provider.
The 2023 Oligonucleotide Therapeutics Society meeting drew 800 attendees to Barcelona, a clear sign that nucleic acid-based drugs are becoming mainstream, especially the oldest technology in this class, antisense oligonucleotides (ASOs). Buzz at the conference centered around the potential of ASO technologies to enable personalized treatments for ultra-rare diseases, many of which are untreatable using traditional small molecule drugs. With a new era of nucleic acid-based drugs and genetic medicines having arrived, many of these diseases could now become treatable.
ASOs work by targeting RNA to alter gene expression, which can modify the expression level or structure of disease-causing proteins in ways that small-molecule drugs can’t. Ten ASO drugs have been approved by the FDA or European Medicines Agency (EMA) since this therapeutic class emerged in the late 1990s, including four that treat Duchenne muscular dystrophy (eteplirsen, golodirsen, vitolarsen and casimersen) and one that treats the neuromuscular disorder spinal muscular atrophy, or SMA (nusinersen).
Many ASO researchers believe this technology holds great promise for the development of “n-of-1” treatments—drugs that are tailored to individual patients based on genetic mutations that are unique to them. One example is milasen, which was developed to treat a variant of Batten’s disease. To realize more successes, biotechnology and pharmaceutical companies, academic medical centers, private foundations and regulatory agencies must first solve several challenges hindering rapid ASO advances. Here are four issues to consider.
Patient Identification, Target Discovery And Lead Compound Identification With AI
Artificial intelligence (AI) has the potential to speed the clinical development of ASOs for n-of-1 and ultra-rare diseases. For example, AI can analyze patient data to identify those who have targetable genetic diseases. Once a target gene/mRNA has been identified, developing an optimal ASO therapeutic is both costly and time-consuming because identifying the ideal target site within an RNA of interest is tricky, sometimes requiring screening of thousands of candidate compounds to ensure efficacy.
However, emerging AI tools could greatly accelerate the discovery of new ASOs while simultaneously lowering costs. AI can help researchers more quickly identify the most promising target sites, slashing the number of compounds that need to be screened. AI can also help researchers analyze mutant genes and predict the best positioning for splice-shifting oligonucleotides, which are designed to remove the section of RNA with the mutation to create a truncated but mostly functional protein.
Technology improvements alone aren’t enough. The pharmaceutical industry, academia and federal agencies should work together to create a federated, decentralized database of affected patients and establish coordinated approaches to discovery that leverage the expertise needed to advance promising targets and therapies. Enabling this approach with AI cannot only create economies of scale but also help get new ASO therapies to patients in need more quickly.
Advances In Oligonucleotide Drug-Delivery Technology
One obstacle limiting the effectiveness of ASOs is that they’re large compounds difficult to deliver to desired target cells. A disease-modifying drug that’s delivered intravenously often doesn’t reach critical therapeutic tissue in sufficient amounts. For example, therapies for Duchenne muscular dystrophy may not have much effect on vital muscles such as the heart and diaphragm. Many genetic diseases affect brain development, so to be effective, therapeutic ASOs must be delivered to the central nervous system via intrathecal injection. Achieving CNS delivery via intravenous injection would greatly simplify the treatment regimen.
Scientists have started working on novel alternatives to address these problems. Researchers are developing cell-penetrating peptides (CPPs) that can attach to ASOs to improve tissue targeting. Others are developing ligands that can cross the blood-brain barrier following simple IV infusion, delivering attached cargo directly into the CNS. More precise and efficient delivery of ASOs to target organs and tissues could transform moderately effective ASOs into life-changing therapeutics.
Development And Manufacturing
Developing an ASO therapeutic, even for a single person, requires high throughput small-scale synthesis of many candidate compounds, followed by medium-scale synthesis of several compounds for animal testing and large-scale synthesis of the final drug. Economies of scale could help reduce the cost of compounds needed during drug development. However, manufacturing of the final drug must be done under current good manufacturing (cGMP) conditions suitable for pharmaceutical use.
Based on my industry experience, manufacturing an oligo-based drug can easily take over a month, with costs exceeding $1 million, for a yield that, depending on dosing, may not be enough to last the lifetime of a patient. Methods to modularize, parallelize, and reduce quality‑control requirements are needed to reduce costs to levels that make the treatment of thousands of rare disease patients feasible.
Regulatory Requirements For N=1 Rare Disease Treatment Compounds
Regulatory approval of new drugs in the U.S. and EU requires compounds to pass rigorous safety testing. This is appropriate for drugs that will be used to treat thousands of people. But what about drugs intended for a handful of people or a single person? New guidelines are under development in the U.S. and the EU to cover the emerging reality of n-of-1 ASO therapeutics but aren’t yet in place.
To support the rapid development of new therapeutics with realistic budgets, these compounds will need to bypass many traditional steps of safety testing. The FDA appropriately requires small molecule drugs with even a single atom changed to undergo full safety re-evaluation. However, ASO drugs could instead be viewed as “drug platforms” rather than individual drugs. These ASO platforms could be standardized up to a point but also allow for variable sequences. That way, ASO developers don’t have to start from scratch with regulators every time they pursue a newly discovered ultra-rare or n-of-1 disease. This could arguably require more limited safety testing before clinical trials, potentially cutting the cost of n-of-1 drug development in half.
The fact is that none of us can do this alone. For more ASOs to be developed and advanced to the clinic, it will take coordinated efforts among researchers, drug developers, technology makers and regulators. Given the remarkable potential of ASOs to treat rare genetic disorders, these efforts could yield breakthrough results for life sciences innovators and the patients they serve.
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