What Goes Inside… Gene and Cell Therapy

Cartoon Virus

After decades of overstated promises and underwhelming results, gene therapies are finally delivering the type of breakthrough therapeutic results that has long excited the scientific and medical world. In late 2017, the world saw the approval of the first gene therapy, Luxterna, which both halts and cures a rare form of blindness. Yes, you heard that right, blindness. Several more gene therapies are in late-stage pivotal trials (Avexis’s Zolgensma for Spinal Muscular Atrophy, and Uniqure’s and Spark’s Hemophilia B programs), looking towards approval in 2019 and 2020 after showing breakthrough efficacy in earlier trials. As a result, KdT has seen a surge of gene therapy companies enter the marketplace. The best of breed of these companies will change the biopharmaceutical landscape forever.

The concept of gene therapy is elegant: like computer bugs, faulty letters in the human genome can be edited and/or replaced with healthy ones. The biopharmaceutical industry has thus far devoted much of their focus in research and development to 1) diseases easily correctable, where only a single letter or gene is defective and 2) vector development. At KdT, we’ve been lucky enough to support companies pushing gene therapy forward in both of these facets, but are excited to do even more.

Complex Disease: At KdT, we have explored utilizing gene therapy to treat complex disease, such as obesity or diabetes, going beyond simple errors in the genetic code while using the toolset of gene therapy. Rejuvenate Bio has cleverly identified a subset of very high-value genes that have shown efficacy across multiple disease areas with remarkable safety profiles to treat complex disease in companion animals. Treating our best friends will validate the capability of using gene therapy to treat us for these diseases as well. However, to go beyond this subset of genes or target broader therapeutic areas, more tools are required.

Vector Development: In order for a gene/therapy to be delivered, it needs to be carried to the tissue and cells of interest by a “vector”. Traditionally, scientists use a virus, specifically Adeno-Associated Virus (AAV), to deliver the gene/therapy to afflicted cells. There are thousands of known — and likely millions of unknown AAVs in nature, thus, one should be able to optimize for the most appropriate vector to deliver the therapy both systematically, to only the designated cells, and successfully, avoiding detection (and death) from our immune system. In theory, this seems trivial — pick the right virus for whatever use you are optimizing for — but in practice, the development and production of different AAVs is extraordinarily difficult. Since a vector is a prerequisite of an effective drug, it makes sense that industry has been very focused on vector optimization over the last several years.

At KdT, we feel that we have reached an inflection point in vector design and optimization. Specifically, companies such as Dyno Therapeutics will saturate the search space for AAVs (as well as potentially other virus types), ushering in an era where the appropriate vector is readily available for virtually any chosen application. Thus the more compelling question is now where are we with what goes inside the vector? If the “Trojan Horse” can now be successfully designed, what do the soldiers look like that will be carried inside?

The Next Generation: Genetic payloads, or the actual code that goes inside the vector, are underdeveloped and underoptimized. This is particularly true when you look at utilizing gene therapy to treat complex diseases. The current state of the art technology has been stalled in development for many years and mainly centers around using new promoters, the part of gene therapy that tells both where and how much to express a certain gene. Innovations have centered around finding new promoters that will only be active in certain cell types (”tissue-specific promoters”) or inducible promoters, essentially promoters that can be controlled using small molecule drugs to turn the gene “On” or “Off”. The simplicity of this setup makes it seem like it should work quite well, but inducible promoters have yet to show promise in animal studies, and we have seen limited control capabilities by current tissue-specific promoters. Solving the promoter equation is one very big challenge and an area of current, intense focus in the field particularly if the goal is to insert a gene and simply “turn it on” or simply produce a machine to “correct the code”. But what about more nuanced functionality/control needed for complex disease? What about a gene or network of genes that equilibrate a cells internal microenvironment?

We expect this fertile ground to be seeded through a wave of technologies currently in their infancy: synthetic promoters, genetic regulatory circuits, and even circular RNA. If you are working on technology in this space, we would love to talk to you!