Breakthrough Techniques Lead to Breakthrough Therapies:
The Role of in vivo Research in Current Cutting-Edge Medical Treatment
IND directed research must adhere to strict requirements for tracking and recording complex statistical, sample, and animal data. These specifications lend a greater degree of oversight, thereby improving accuracy and confidence in the results of critical in vivo testing. The interplay between metadata tracking, drug discovery software, and in vivo research is critical to the future of countless patients and the pharmaceutical and healthcare industries. Optimizing this process by using a state-of-the-art database system can dramatically improve efficiency while evaluating and managing complex data thereby reducing time to FDA approval.
To that end, the most sophisticated biomedical techniques and drug therapies owe their development and utilization to in vivo research. Here we highlight the groundbreaking techniques of CRISPR/Cas9, immunotherapy, and RNA therapy, and the some of the treatments they helped to develop, thanks to in vivo research.
Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) uses the CRISPR-associated protein 9 (cas9) endonuclease and guide RNA to alter DNA and treat disease. This is achieved through non-homologous end-joining or homology directed repair. The former cleaves a portion of DNA resulting in disruption or deletion of DNA, while the latter couples a Cas 9 guide RNA with a DNA template, which is then utilized as a replacement in the normal repair process.
CRISPR was recently used to treat Leber congenital amaurosis type 10, caused by mutations in the CEP290 gene. The pioneering procedure, conducted at Oregon Health and Science University Casey Eye Institute, is the first instance of in vivo gene editing in a human (OHSU). This revolutionary accomplishment is the result of decades of CRISP/Cas9 in vivo research and opens myriad avenues for novel treatments to gene-linked diseases thought untreatable.
Immunotherapy harnesses the body’s innate immune system to treat disease, and currently represents a new breakthrough therapeutic strategy in oncology. One of the most recently approved cancer treatments utilizes Chimeric Antigen Receptor (CAR) T-cell Therapy and has shown great efficacy in leukemia and lymphomas. CAR-T therapy harvests the patient’s own T cells via apheresis and genetically modifies them to express CARs, which bind to targeted surface antigens on cancer cells thereby allowing the T-cells to better recognize and destroy cancer cells.
Though promising, CAR-T therapy can have serious side effects and limited application, having shown very little efficacy in solid tumor models, which account for over 90% of cancers. Pre-clinical in vivo research will play a vital role in re-engineering CARs for greater applicability, efficacy and safety. (The reader is referred to Lee, Young-Ho & Kim, Chan Hyuk, 2019 for a comprehensive review of CAR-T therapy)
Ribonucleic acid (RNA) has many forms, perhaps the most widely known being mRNA – the product of transcribing DNA so that it may be translated into protein. Laboratory synthesized mRNA can be used to induce protein production within a cell, while RNA interference (RNAi), and antisense oligonucleotides (ASO) are currently the primary RNA tools used to develop therapies reducing production of the target protein. In combination with its high specificity, as above in CRISPR/Cas9, these methods are ideal candidates for novel drug development.
The COVID-19 pandemic has thrust RNA therapies into the limelight. By exploiting the cell’s translation of exogenous mRNA into the SAR-CoV-2 spike protein, the body can launch an immune response to the COVID-19 virus. While it is yet undetermined how long the body will “remember” the spike protein, transmission and diagnosis of COVID-19 has dropped dramatically in regions where the vaccine has been widely administered.
The rapid development of the COVID-19 vaccine required an expedited process that began with in vivo research. Results were replicated internationally using successively higher order animals (Talukder & Chanda, 2021) while concurrently beginning phase I clinical trials. Through this concentrated effort, scientists were able to engineer a novel and efficacious RNA vaccine that can be built upon for future vaccines and disease therapy.
These technological and medical breakthroughs would have been impossible without established and new in vivo methods. Together with advanced comprehensive software to create and track experiments and data, future collaborations like those resulting in CRISPR/Cas9, immunotherapies and RNA treatments can get to market, and patients, faster and at lower cost.
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Lee, YH., Kim, C.H. Evolution of chimeric antigen receptor (CAR) T cell therapy: current status and future perspectives. Arch. Pharm. Res. 42, 607–616 (2019). https://doi.org/10.1007/s12272-019-01136-x
Talukder, P., Chanda, S. RNAi Technology and Investigation on Possible Vaccines to Combat SARS-CoV-2 Infection. Appl Biochem Biotechnol 193, 1744–1756 (2021). https://doi.org/10.1007/s12010-021-03548-2