A novel approach to improve the safety and efficacy of gene-based immunotherapy

TheraPlas is a technology platform for the delivery of DNA and messenger RNA (mRNA) therapeutics via synthetic, nonviral carriers. Capable of providing cell transfection with double-stranded DNA plasmids and large therapeutic RNA segments, it represents a novel approach to improving the safety and efficacy of gene-based therapies.

A distinct, viable alternative to current gene delivery approaches

There are 2 components of the TheraPlas system: a plasmid DNA or mRNA payload encoding a therapeutic protein, and a delivery system. Based on a chemically modified low-molecular-weight polymer, the delivery system is designed to protect the DNA/RNA from degradation and promote trafficking into cells and through intracellular compartments. Biocompatibility of the polymers reduces the risk of adverse immune reactions, allowing for repeat administration. Compared to naked DNA or cationic lipids, TheraPlas is generally safer, more efficient, and more cost effective.

The design of the TheraPlas delivery system is based on molecular functionalization of polyethyleneimine (PEI), a cationic delivery polymer with a distinct ability to escape from the endosomes, due to heavy protonation. The transfection activity and toxicity of PEI is tightly coupled to its molecular weight, heretofore limiting its clinical application. We have used molecular functionalization strategies to improve the activity of low-molecular-weight PEIs without augmenting their cytotoxicity.

Another approach to improve PEI activity involves crosslinking low-molecular-weight PEIs through degradable linkages, to create larger and degradable structures. Two cross-linked polymers have been synthesized with this approach and optimized for transfection activity. Both cross-linked polymers expressed several-fold higher transfection activity than their respective monomers and lower cytotoxicity than a commercially available 25 kDa polymer.

Products utilizing TheraPlas: GEN-1

GEN-1 is the first product designed using the TheraPlas platform technology. It is a gene therapy that combines TheraPlas with the interleukin-12 (IL-12) plasmid. Its nanoparticle profile enables cell transfection followed by persistent, local secretion of the IL-12 protein at therapeutic levels while avoiding the toxicities associated with recombinant IL-12.

GEN-1 is currently being evaluated in clinical programs for patients with ovarian cancer and has also demonstrated potential efficacy benefits in glioblastoma multiforme (GBM).