Although CRISPR has become increasingly synonymous with a disease-free future, there are issues pertaining to the control of the technology that could impact its future influence in the world of science.
The Good: Recent Clinical Successes
CRISPR/Cas-9 has had many clinical successes that have proven the technology’s worth in the world. CRISPR’s current clinical successes have been in hemoglobinopathies, including β-thalassemia and sickle cell disease (SCD). For example, CTX001 is a Cas9 gene-edited hematopoietic stem cell therapy and is designed to increase levels of fetal hemoglobin (HbF), a natural form of hemoglobin present in humans before birth. HbF can substitute for the impaired hemoglobin in β-thalassemia and SCD patients and, thereby, reduce or eliminate symptoms.1 A safety and efficacy study showed that CTX001-modified CD34+ human hematopoietic stem and progenitor cells could engraft in patients with thalassemia and SCD and improve their symptoms.2
CRISPR/Cas9 is also proving beneficial for oncology. CTX110 is an allogeneic gene-edited CAR-T product. Specifically, CTX110 targets CD19, an antigen expressed in various B-cell malignancies.3 CD19 plays a critical role in B cell development and maturation. Studies have shown that CD19 “plays an active role in driving the growth of [B- cell] cancers, most intriguingly by stabilizing the concentrations of the MYC onco-protein.” 4 The anti-CD19+ Car- T therapy shows the potential of CRISPR technology and how it can revolutionize medicine. The results from the Phase 1 CARBON trial evaluating the efficacy and safety of CTX110 have been very promising. CTX110, “according to Joseph McGuirk, D.O., Professor of Medicine and Division Director of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center and investigator in the Phase 1 CARBON trial of CTX110, ‘has shown dose-dependent efficacy and response that is comparable to the early autologous Car-T trials. Furthermore, CTX110 had an acceptable safety profile that could make Car-Ts more widely accessible’.” 5
As the recent clinical successes show, proponents of CRISPR/Cas9 believe it can improve a wide variety of illnesses.
The Bad: CRISPR Ownership
There is an ongoing dispute over the ownership over the foundational patent rights to CRISPR-Cas9 gene-editing technology. 6 During the course of this dispute, MIT, Harvard, and The Broad Institute haven’t wasted any time in granting exclusive licenses to their own surrogate companies, which in turn are able to grant individual licenses to third-parties. The exclusivity of the patents issued is not what is concerning. Instead, the concerning factor is that the exclusive licenses “are for every gene in the human body and every gene known to humankind.” 7 The exclusive licenses granted to the institutions’ own surrogates limit access to CRISPR as a platform technology, potentially hindering completion and creating innovation bottlenecks” 6 Professor Jorge Contreras of The University of Utah along with Jacob Sherkow of New York Law School, wrote in a 2017 Science article. The exclusive patents would cause independent biotechnology companies to submit development plans to the universities for approval. The universities, in turn, could accept or deny the plans, effectively controlling what type of research is done. With only a couple of universities having legal patent rights to CRISPR technology, the amount of research that will be done using CRISPR will be significantly minimized. Every new and novel therapy will have to go through a lengthy approval process with the universities. It is unlikely that the universities will be willing to approve every proposal they receive, meaning that all the possible research that could’ve used CRISPR will be unable to begin.
The Ugly: Unrealistic Solutions
Bioinsider discussed with Prof. Jorge Contreras the possible solutions and how realistic they are so that there is healthy competition and hence, significant progress for CRISPR-based technologies.
There are several possible solutions to the patent dispute, and each has its own effect. One of the possible solutions to this dispute is the Bayh- Dole Act. The Bayh- Dole Act states that a company must “grant the government a nonexclusive, irrevocable, paid-up license to use the Subject Invention throughout the world, require substantial manufacture in the U.S. for any exclusive licensee, allow the U.S. government to exercise March-In Rights, i.e., the government can require the contractor to license the patent to others on reasonable terms and comply with the administrative components of the law.” 8 Prof. Jorge Contreras, in the interview, explained that there are certain instances such as supply chain issues that could allow the NIH to implement ‘march-in rights’ or if there is a public health need. However, Prof. Jorge Contreras commented that “even when there have been [supply problems], the NIH has never exercised these rights” 9 Hence, it is unlikely that the government would take action for this particular patent dispute.
Diligence milestones could also be of use. They “require an exclusive licensee to demonstrate progress toward commercialization of a licensed technology ( often through the achievement of various regulatory hurdles, testing, and trials).6 According to Prof. Jorge Contreras, “diligence milestones as a concept can be very strict or very lenient. It all depends on who wants to enforce them. The problem with surrogate companies is that there is usually a cozy relationship between the company and the university, usually because the company founder is on the faculty. That faculty member is often the one who knows most about the technology, so the likelihood that the university will claim that they didn’t meet diligence milestones is low.” 9 In theory, diligence milestones are the best way to monitor the companies that have received exclusive rights to patents. However, in the case of CRISPR, diligence milestones are not being enforced properly, which renders them useless.
What can realistically be done?
One area where partnering is possible is in the area of drug delivery. Unfortunately, CRISPR-Cas9 currently cannot be delivered systemically to target diseased tissue. New and significant advancements in in-vivo systemic delivery methods are being researched. Academics in delivery technology will have strong intellectual property licenses that the holders of the CRISPR/IP cannot disregard. Typically, multiple inputs (IPs) are needed to make a single product. With numerous inputs required to make a single product in most cases, the exclusive licenses’ effectiveness will be put to the test. The universities will either have to make exceptions in these cases and go against their own exclusive licenses or change the licenses’ exclusivity altogether. It has yet to be seen as to what these universities would do in this case.
To sum up, CRISPR has changed the future of medicine and treatment possibilities for multiple illnesses. Successful clinical trials have shown CRISPR’s capabilities. Yet, the patent dispute has revealed something more concerning: universities’ sole focus to rein in the technology and control its research usage. Only time will tell what the future of CRISPR holds and how it will impact the world as a whole.
About the author:
Nicole Ludwiak is enthusiastic about emerging cancer therapeutics and the potential of technology to advance medical research.
- Hemoglobinopathies. (2019, August 30). CRISPR. http://www.crisprtx.com/programs/hemoglobinopathies
- Initial Safety And Efficacy Results With A Single Dose Of Autologous Crispr-Cas9 Modified Cd34+ Hematopoietic Stem And Progenitor Cells In Transfusion-Dependent Β-Thalassemia And Sickle Cell Disease. (2020) Multilearning Group Inc. https://bit.ly/3cOxhLe
- Pipeline. (2020, October 28). CRISPR. http://www.crisprtx.com/programs/pipeline
- CD19-The Most Popular Target with CAR T-Cell Therapy. (2021). Cusabio. https://www.cusabio.com/c-20949.html
- Reports Positive Top-Line Results from Its Phase 1 CARBON Trial of CTX110TMin Relapsed or Refractory CD19+ B-cell Malignancies. (2020). CRISPR Therapeutics. https://crisprtx.gcs-web.com/news-releases/news-release-details/crispr-therapeutics-reports-positive-top-line-results-its-phase
- Surrogate Licensing, and Scientific Discovery, CRISPR Vol. 355, Issue 6326, pp. 698-700 (2017). Contreras, J. L., & Sherkow, J. S. https://doi.org/10.1126/science.aal4222
- Exclusive CRISPR licenses slow development of therapies, legal experts argue. (2020, January 17). SciPol.Org. https://scipol.org/news/exclusive-crispr-licenses-slow-development-therapies-legal-experts-argue
- Basics of the Bayh-Dole Act. (2021). Wilson Sonsini Goodrich & Rosati Professional Corporation. https://www.wsgr.com/en/insights/basics-of-the-bayh-dole-act-faqs.html
- Contreras, J. (2021, February 15). Personal Interview.