Expanding the Drug Delivery Toolbox

Today our ability to treat many diseases is limited only by our ability to effectively deliver genetic medicines.

Patients treated with genetic medicines receive nucleic acids, either DNA or RNA, to fix, replace or fine tune the expression of certain genes. By supplying patient cells with new functional copies of genes or fixing mutated genes, genetic medicines provide the biological “source code” to not only treat, but to cure disease. These programmable medicines have the potential to address unmet needs for millions of patients, including those with rare genetic diseases for which few effective treatments are available.

With 8 FDA approved therapies and 120 more in at least phase II trials, viral vectors are currently the standard delivery system for genetic medicines, of which, the adeno-associated virus (AAV) is the most common. Viral-delivered gene therapies have demonstrated clinical benefit across a range of genetic diseases; however, their ability to unlock the full potential of genetic medicine faces significant limitations:

1. Immunogenicity: Viral delivery systems encapsulate therapeutic cargos (proteins, DNA, and/or RNA) inside a viral capsid which the immune system can recognize as foreign. Immune recognition and elimination of viral capsids limits both initial delivery of the drug and the ability to re-dose it.

2. Safety: Over a third of AAV gene therapy clinical trials have reported serious adverse events (SAEs) including liver toxicity and severe inflammation. These SAEs were caused by the non-native nucleic acids, the viral capsid, or the immune system’s response to these components. Tragically, just this month, two children died of acute liver failure within 5 weeks of taking Novartis’s AAV-gene therapy, Zolgensma, for spinal muscular atrophy.

3. Size/Delivery Capacity: Delivery by viral vectors presents a packing problem: genetic medicine cargos must fit within the viral capsid. 83% of genes are not viable for AAV gene therapy because they exceed the AAV’s ~4.2 kb cargo capacity.

4. Cell Specific Delivery: Delivery by viral vectors is still too limited to certain privileged cell types (for example, the eye and the liver). Our collective ability to deliver therapeutic payloads to other cell types (and only those specific cell types) remains more aspirational than resolved.

While viral vectors have effectively been used to deliver nucleic acid-based drugs to patients, they are not one size fits all. Next-generation biologics and genetic medicines need a robust toolbox tailored to address specific diseases, once the “low hanging fruit” are all gone. They’ll need a delivery platform that is customizable for targeted cell delivery, has a favorable safety profile, and is adaptable to a wide breadth of therapeutic modalities.

Non-viral vectors have the potential to provide benefits where viral vectors are limited. The genes driving Parkinson’s Disease, Duchenne Muscular Dystrophy and Stargardt Disease all exceed the capacity of a single AAV vector, but not non-viral vectors. Further, non-viral systems can deliver a greater level of therapeutic diversity (e.g., DNA, RNA, entire proteins, and protein-nucleic acid complexes) than even the best current viral vectors. The cargo capacity and flexibility of non-viral vectors opens the door to pursue “undruggable” targets and impact previously untreatable diseases. For example, autoimmune diseases or cancers are prime targets for non-viral vectors given their need for redosing and more tightly controlled therapeutic indexes. Non-viral delivery systems are a potential swiss army knife offering the flexibility needed for next-gen therapies.

The most promising non-viral delivery systems currently fit into three main classes:

References: 1 & 2. Figure 1. Breakdown of non-viral delivery classes

While we have identified and celebrated the virtues of these non-viral delivery systems, there are still significant challenges to overcome prior to realizing their vast potential:

Among the three classes of non-viral delivery systems, EVs are uniquely “platformable”. Because they originate from genetically programmed producer cell lines, EVs are theoretically easier to engineer with specific characteristics than LNPs, which must be synthetically formulated using rigid chemistry. Genetically programmed EV biogenesis lends itself to a model of iterative, AI-assisted design-test-learn cycles to efficiently optimize EVs for delivery.

Of the three non-viral delivery modalities discussed above, we believe EVs have the greatest potential to fill the void left by viral vectors. However, in addition to the obstacles described above, there other potential hurdles unique to EVs that will require further optimization:

Every month new biotech companies emerge from stealth aiming to solve non-viral delivery. Propelled by an increasingly interested set of capital investors, the pace of innovation has the potential to be exponential. Below is just a sample of groups focused on solving delivery with non-viral vectors.

Figure 2. Biotech companies innovating in the non-viral delivery space.

Non-viral delivery systems currently teeter at a critical inflection point. We’ve come a long way in understanding what components are required to build a delivery system, but that knowledge has yet to translate into safe, effective non-viral delivered therapies. Winners in the non-viral delivery space will build rational solutions to deliver the next generation of drugs and biologics. They will combine advances in DNA synthesis, high-throughput screening and ML/AI to query the entire search space of possible vector designs, akin to Dyno Therapeutics’ CaspidMap Platform, which led the wave in AAV vector-fitness mapping and design. With an efficient design-test-learn cycle, they will be able to understand how each individual piece of the non-viral vector contributes to its function in vivo. The winners will be able to iterate this cycle in the fastest, most efficient manner to optimize for biodistribution, targeted cell delivery, efficient cargo loading and release, and safety.

While today’s viral delivery methods are equipped to treat a subset of disease types, the future biotech delivery toolbox needs a more robust toolset. We believe that non-viral vectors, especially EVs, are primed to be the swiss army knife of delivery and usher in this next generation of therapies.

Authors: Emilio Ferrara and Tamara Vital, KdT Ventures

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