The field of gene therapy is experiencing renewed focus and many companies have been formed in the last decade to pursue the promise of this approach. Gene therapy involves the delivery of nucleic acids—either DNA or RNA—into a cell to effect changes in cell function that have therapeutic benefit. Originally, this approach was used to genetically alter bacterial, fungal or human cell lines to make different kinds of therapeutic proteins that were delivered to patients (biologic therapy). More recently, human cells outside the body have been genetically altered and then delivered to patients as therapy (cellular therapy). Gene therapy is an evolution of this approach where the alteration of human cells is performed inside the body. The most recent offshoot of this approach is to deliver a gene-editing platform, such as TALEN or CRISPR/Cas9 into cells to alter the genome of a patient for therapeutic purposes (genomic therapy).
Gene therapy involves four main approaches. In gene augmentation therapy, DNA is delivered to cells to restore normal cellular function. This is typically used to correct a genetic defect that has results in the loss of production of a protein or the generation of an abnormal protein. Gene inhibition therapy involves using nucleic acids (e.g., siRNA, miRNA) to turn off unwanted cellular functions. Genetic cytotoxic therapy involves delivery of nucleic acids into cells targeted for elimination (like cancers) by directing the cell toward programmed cell death.
The final major approach, gene encoded therapeutics, involves delivering nucleic acids into cells (either RNA or DNA) that will induce the cells to produce a therapeutic protein. Such genetic alterations are transient—cells only produce the therapeutic protein of interest for a limited period of time. Gene-encoded therapeutics eliminates the need for developing a recombinant therapeutic protein—the body itself becomes the factory for protein production. SmartPharm Therapeutics is focused on gene-encoded therapeutics.
Gene-encoded therapeutics (GETs) is a recent emphasis within gene therapy. First-generation attempts to produce therapeutic proteins in the bodies of the patients have encountered practical obstacles. Each of the two types of nucleic acid platforms—plasmid DNA and messenger RNA—has key limitations. DNA plasmids typically need to penetrate into the cell nucleus to function and often only small quantities are delivered there. Concerns about the potential for integration of the DNA into the cellular genome is always a safety/regulatory concern. DNA GETs usually yield low expression of the protein of interest, but the duration of expression can be quite long. DNA plasmids are also capable of containing large amounts of genetic information, making it possible to produce large proteins or multiple proteins.
In contrast, messenger RNA (mRNA) GETs do not need to get into the nucleus. They are constitutively safer from this perspective and more readily result in high-yield protein expression by the cell. However, the duration of expression tends to be short and the amount of genetic information that can be transmitted in each mRNA construct is limited.
Delivery of DNAs or RNAs by themselves are relatively inefficient. Therefore, specialized carriers, such as liposomes or nanoparticles, are used to protect the nucleic acids outside the cell and help it get into the cytosol inside the cell. Another approach has been to use electroporation to induce the delivery of the nucleic acid into the cell. While this has been successful in some clinical trials, we do not consider electroporation to be a clinically-viable approach for wide application of GETs.
An alternative approach is to incorporate the DNA or RNA into a viral construct that is evolutionarily designed to penetrate the cell and, in the case of DNA, to deliver the DNA into the nucleus. While the use of these viral vectors increases delivery efficiency, their use comes with safety concerns, and in most cases the body will mount a multi-pronged defense against these viruses. Especially in the case of repeat or chronic gene-encoded therapy, immune suppression therapy may be needed along with the GETs. This therapy itself comes with clinical risks. Finally, viral vectors carry very limited genetic information and large-scale production is both technically challenging and expensive.
GET Therapeutic Platforms
Advantages/Disadvantages of Different Types of GETs