Trevor Smith, VP of Preclinical R&D at INOVIO Pharmaceuticals, discusses the potential of DNA medicines, the importance of delivery technology, and the challenges involved in translating promising preclinical science into clinical therapies.
At INOVIO Pharmaceuticals, Trevor Smith leads a team of preclinical scientists developing DNA-based medicines across a range of disease areas. A major focus is the in vivo delivery of plasmid DNA constructs designed to enable the body to produce functional therapeutic proteins, with the broader goal of addressing significant unmet medical needs.
Why DNA Medicines?
Smith believes DNA medicines have progressed beyond simply being a promising concept. The platform has potential applications spanning immunotherapy, rare diseases, infectious diseases, and conditions currently treated with gene or protein replacement therapies.
One important advantage is the ability to use the body's own cells as biological "factories." Following delivery of DNA constructs, muscle cells can produce and secrete therapeutic proteins such as antibodies for sustained periods.
INOVIO has also explored DNA-encoded protein approaches for diseases requiring long-term therapeutic coverage. Preclinical programs include production of Factor VIII for hemophilia A and replacement of missing or defective enzymes in rare diseases such as Fabry disease.
A key potential benefit is redosing. Unlike some viral-vector gene-delivery approaches, DNA-based platforms may allow treatment to be administered repeatedly, potentially giving physicians greater flexibility in managing long-term diseases.
Delivery Is Central to the Platform
Delivery technology is critical to unlocking the therapeutic potential of DNA medicines.
INOVIO's approach combines plasmid DNA constructs with an enhanced delivery system based on electroporation, which helps DNA enter cells efficiently. Effective delivery can determine how much therapeutic protein is ultimately produced, how consistently it is expressed, and how durable that expression becomes.
For DNA medicines, therefore, the construct itself is only part of the equation. Optimizing delivery parameters and dosing is equally important in achieving therapeutically meaningful levels of protein expression.
The Preclinical Translation Challenge
One of the biggest challenges in advancing DNA-based therapeutics is translating laboratory findings into living systems.
According to Smith, conventional in vitro experiments provide limited insight into the levels of protein expression that will ultimately be achieved in vivo. They also cannot fully capture how a gene-delivery system will perform within a living organism.
INOVIO's preclinical teams have therefore spent years designing and refining in vivo models that can evaluate delivery conditions, dosing parameters, expression levels, and overall biological activity. These models are intended to help identify the conditions required to produce consistent therapeutic protein levels before candidates move into clinical development.
What Comes Next?
Smith highlights INO-3107, INOVIO's DNA immunotherapy candidate for Recurrent Respiratory Papillomatosis, as an important program for demonstrating the broader potential of the platform. A BLA for INO-3107 is currently in review under the FDA’s accelerated approval program with a target PDUFA action date of October 30.
Beyond immunotherapy, he sees considerable opportunity in the company's next-generation DNA-encoded protein, or DPRO, technology. Programs targeting hemophilia A and Fabry disease are designed around a compelling concept: enabling patients to produce therapeutic proteins within their own bodies rather than relying on frequent injections of recombinant biologics.
If advances in DNA construct design, electroporation, dosing, and predictive in vivo models continue to converge, DNA medicines could offer a differentiated approach to long-term gene delivery and protein replacement.
