Astera Bio focuses on innovative preclinical and early clinical companies in the cell and gene therapy (CGTx) space. Figure 1 below depicts the large amount of attrition from drug development and its relevant phases (from target validation to drug application submission). It is at these early critical junctures (from preclinical to Phase 1/2 readouts) that the largest return can be captured. We leverage our expertise in the space, and our ability to discern the likelihood of clinical translational success. Additionally, early biotechs in the cell and gene therapy space are poised for outsized growth as the potential of the technology is just beginning to be appreciated. As the technology has the ability to supplant current outdated pharmacologic strategies, CTGx companies are also becoming acquisition and merger targets of large Pharma providing another avenue for positive returns.
Astera Bio invests in multiple areas of the cell and gene therapy space. Overarching themes include gene therapy (DNA delivery or editing), gene silencing or modulation (RNA therapies) and cell therapies (replacement or augmentation of cell populations with programmed or repaired cell types).
Fig. 1: Drug Developmental Process from: Pharm. Bioprocess. (2013) 1(1) 29-50
Gene Therapy (Rx)
DNA is delivered into cells via vectors, such as viruses that include various subtypes, each with different tissue affinity and strengths/weaknesses; the two most common viruses include Adeno-associated virus (AAV) and Lentivirus. Non-viral vectors include vesicles comprised of fats (lipids) and proteins that provide a protective shell in the circulation but are taken up by cells where the payload “DNA or gene” is delivered. A significant amount of pre-clinical research is dedicated to developing better non-viral vectors, as well as safer more targeted viruses for gene delivery to specific organs or tissues. Regardless of vector, genes are delivered and expressed in target cells to replace abnormal DNA in order to treat and ideally cure the genetic disease. The key with gene therapy is targeting the therapy to the cells that are diseased from the mutant DNA, e.g. blood cells in sickle cell anemia, liver cells in metabolic disease and neuronal cells in central nervous system (CNS) diseases. Current vectors are excellent at targeting organs involved in the dieases described, but fall short of treating other organ compartments. Next generation gene therapy technology (being developed in academia and the private sector) is focused on developing better vectors that can be targeted to any tissue type and thus opening up many more diseases for gene therapy.
Gene Editing
DNA editors including CRISPR enzymes and previous editing tools (TALENs and zinc finger nucleases (ZFNs)) can be delivered using gene therapy vectors, where DNA encoding the CRISPR machinery is delivered. The editors are then guided to the aberrant DNA to “fix” the target cell’s DNA code permanently. While the first set of CRISPR enzymes have shown proof of concept, there remains many variations of the tool that are being explored. CRISPR 1.0 cuts both strands of DNA requiring innate error-prone cellular repair mechanisms to complete the process. Additionally, CRIPSR 1.0 can cut erroneously in other areas of the genome, potentially introducing “off target” effects. It has been described as a powerful but somewhat clumsy tool. Next gen DNA editing includes prime and/or base editing where precision is its strength. It includes additional enzymes to the CRISPR suite that allows for single DNA strand cuts with single base editing. The difference may be likened to exchanging a single keyboard key versus replacing the entire panel. While there is one public company utilizing this new technology (Beam Therapeutics), there are many in the private sector working on variations on the theme, and we expect to see a lot of innovation in this specialized technology.
RNA
RNA molecules have various applications as RNA can be delivered to the cell but does not need to be integrated into the cell’s nucleus like DNA. RNA molecules also have a myriad of functions. siRNA (small interfering RNA) or ASOs (anti-sense oligonucleotides) can be delivered directly into the bloodstream. They are chemically modified to hone to target organs and designed to silence “mutant” RNA molecules made from defective genes. However, similar to DNA vectors, silencing RNA delivery is somewhat restricted to accessible tissue types that include the liver, CNS, and blood. Another RNA type is mRNA (messenger RNA) which can at times substitute for DNA delivery. As DNA is transcribed to mRNA, mRNA delivery skips a step and delivers the message directly. One issue however is that mRNA molecules are too large for traditional viral vectors and require specialized vectors. It is this mRNA technology that is a main focus in vaccine development where, for example, mRNA encoding the viral proteins for COVID-19 are being delivered to cells where the COVID-19 protein is made and presented by host cells to elicit an immune response. There are also new private sector developments in miRNA, microRNA, that can modulate DNA gene expression. Thus, RNA is the swiss army knife of genetic therapies. As such it’s a versatile and nimble tool, but unlike DNA which could be curative, RNA requires re-dosing (albeit relatively infrequent dosing, e.g. monthly, every 3, 6 or 12 months, compared to traditional therapeutics of daily or weekly).
Cell Rx
The vectors and DNA technologies outlined above can be used to manipulate cells outside the body (in vitro), or for transplantation into the body (in vivo) to treat disease. The most successful technology has been chimeric antigen receptor T cell (CART) therapy where either a patient’s immune cells (autologous) or donor cells (allogenic –from either a live donor or from cells grown and differentiated in a laboratory) are manipulated to trigger an immune response to certain tumors as an Immuno-Oncology (IO) therapy. Next generation CART includes newer technology to use allogenic (off the shelf) cells of different types and different immune engagement mechanisms to target specific tumors. These cells can be derived from iPS (induced pluripotent stem cells) or from other donor cell types such as natural killer (NK) cells. The various cell types can leverage different cellular skill sets and tumor targeting which ideally will be specifically tailored to tackle cancer more efficiently.