Fundraising net proceeds go to COVID-19 Solidarity Response Fund for WHO

The Good, the Bad, and the Ugly: Is the Future of CRISPR Certain?

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.

Bayh-Dole Act

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

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.

Conclusion

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. 

 

References :

  1. Hemoglobinopathies. (2019, August 30). CRISPR. http://www.crisprtx.com/programs/hemoglobinopathies
  2. 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
  3. Pipeline. (2020, October 28). CRISPR. http://www.crisprtx.com/programs/pipeline
  4. CD19-The Most Popular Target with CAR T-Cell Therapy. (2021). Cusabio. https://www.cusabio.com/c-20949.html
  5. 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
  6. 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 
  7. 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
  8. 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
  9. Contreras, J. (2021, February 15). Personal Interview.
Share on linkedin
LinkedIn
Share on twitter
Twitter
Share on facebook
Facebook
Share on xing
XING
Share on email
Email

You may also be interested in...

James E. Crowe, Jr., MD,

Director, Vanderbilt Vaccine Center; Professor, Pediatrics and Pathology, Microbiology and Immunology, Ann Scott Carell Chair; Founder, IDBiologics

Dr. Crowe’s laboratory has a broad portfolio of work in the area of viral immunology and antibody sciences, with the goal to discover mechanisms of immunity important to developing new therapeutics and vaccines.

Dr. Crowe received his MD degree from the University of North Carolina at Chapel Hill, where he also completed his pediatrics residency. Following his clinical training, Dr. Crowe received five years of post-doctoral training in the laboratory of Infectious Diseases at the NIH. He completed infectious diseases fellowship training in 1996 at Vanderbilt and has run an independent laboratory at Vanderbilt since that time. He is currently Professor of Pediatrics and of Pathology, Microbiology and Immunology, and the Ann Scott Carell Chair, Vanderbilt University Medical Center. The laboratory’s work has been published in over 300 publications in high-quality science journals including CellScience and Nature, and leading medical journals including the New England Journal of Medicine and JAMA. Dr. Crowe was elected to the National Academy of Medicine in 2014 and the National Academy of Inventors in 2017. He has been the recipient of investigator awards from the March of Dimes, American Society for Microbiology, Pediatric Infectious Diseases Society, and Society for Pediatric Research. He was awarded the Judson Infectious Daland Prize of the American Philosophical Society, the Oswald Avery Award of the IDSA, the E. Mead Johnson Award for Excellence in Pediatrics, the Outstanding Investigator Award of the American Federation for Medical Research, the Norman J. Siegel Award of the American Pediatric Society, the Samuel Rosenthal Prize for Excellence in Academic Pediatrics, the Stanley J. Korsmeyer Award of American Society for Clinical Investigation, the Distinguished Medical Alumnus Award from UNC School of Medicine, Chapel Hill, NC. He is an elected Fellow of AAM, AAAS, ASCI, and AAP, IDSA, APS, and others. His research team was selected as the Best Academic Research Team at the 11th Annual Vaccine Industry Excellence Awards. He was awarded the inaugural 2019 Merck Future Insight Prize, a 1M Euro prize shared with Pardis Sabeti. 

He is the Founder of IDBiologics, Inc., an early-stage biotech company developing human monoclonal antibodies for infectious diseases.

Daniel Chen, MD, PhD

CMO, IGM Bioscience

Daniel S. Chen, MD, PhD, is the Chief Medical Officer for IGM Biosciences, and former Vice President, Global Head of Cancer Immunotherapy Development at Genentech/Roche.  He received a BS degree in Biology from the Massachusetts Institute of Technology (1990), a PhD in Microbiology & Immunology (1996), and MD (1998) from the University of Southern California. His PhD work and publications focused on “Early Events in Coronavirus Infection.”

Daniel completed an Internal Medicine Residency and Medical Oncology Fellowship at Stanford University (2003). He went on to complete a Post-doctoral fellowship with Mark Davis in Immunology, where he was a Howard Hughes Medical Institute Associate. He also ran the metastatic melanoma clinic at the Stanford Cancer Center from 2003-2006. In that time, he studied human anti-cancer immune responses pre- and post-cancer vaccination and cytokine administration to determine why anti-tumor immune responses were not more clinically effective. He received a U19 grant to develop better immunologic tools to interrogate human immune responses and ultimately patented the MHC cellular microarray to detect and functionally characterize antigen-specific T cell states.

He continued as Adjunct Clinical Faculty at Stanford from 2006-2016, where he cared for melanoma patients. At Genentech from 2006-2018, Daniel focused on the clinical development of anti-angiogenic and immune-modulatory targeted therapies in both early and late development, as well as the diagnostic tools to aid their development. This included leading the clinical development for atezolizumab, a PD-L1 inhibitor, from the time the program was in research through IND, Phase I, Phase II, Phase III, to filing and approvals in multiple indications worldwide. At IGM, Daniel focuses on the development of novel engineered multivalent and multispecific therapeutics. He is a reviewer for Nature, Immunity, and Clinical Cancer Research, serves on the Board of Directors for SITC, co-chair of the CRI cancer Immunotherapy consortium, gave the keynote presentation at the AACR NCI EORTC Annual Meeting 2014 and presented at the US Congressional Briefing on Immuno Oncology in 2017. He has continued to publish with academic and industry collaborators in the field of cancer immunotherapy, including the often-referenced Chen and Mellman manuscripts, “Elements of cancer immunity and the cancer-immune set point” and “Oncology meets Immunology: The Cancer-Immunity Cycle.”

Imre Berger

Founding Director, Max Planck Bristol Centre; Chair in Biochemistry and Chemistry; University of Bristol UK

Imre Berger was trained as a biochemist and synthetic biologist at Leibniz University and Medical School (MHH) in Hannover (Germany), at MIT (Cambridge, USA), and at ETH Zurich (Switzerland). Imre’s team develops enabling methods for DNA delivery and genome engineering, engineers synthetic vaccines and nanosensors and researches the structure and mechanism of multiprotein complexes in human health and disease. After Group Leader posts at ETH (2005) and EMBL (2007), Berger joined Bristol as Full Professor of Biochemistry (2014) with a joint appointment in Chemistry (2019). He is Founding Director of the Max Planck Centre for Minimal Biology in Bristol, Director of the BBSRC/EPSRC research center for synthetic biology BrisSynBio and Co-director of the Bristol Biodesign Institute BBI.

Imre Berger holds international patents for DNA and protein technologies, co-founded three biotech companies, and received numerous distinctions, notably the Swiss Technology Award, the W.A. DeVigier Foundation Award, and a Wellcome Trust Senior Investigator Award for his innovative research. Since 2019, he is an Investigator of the European Research Council (ERC).

Prof. Berger has participated in leading roles in numerous European Commission (EC) projects, including the pan-European structural biology infrastructure INSTRUCT. He has been Coordinator of the EC FP7 HEALTH ComplexINC project enhancing production tools for complex biologics in academic and industrial R&D (2011-2016) and is partner in the EPSRC funded Innovative Future Vaccine Manufacturing Research Hub.

Sina Bavari, PhD

CSO, Edge BioInnovation Consulting and Management; former CSO, Scientific Director US Army Medical Research Institute of Infectious Diseases (USAMRIID)

Dr. Sina Bavari is the co-founder of Healion Bio. He is one of the lead (non-gov) scientific adviser to the World Health Organization on SARSCoV-2. He has spent over 30 years developing rapid response diagnostics, prophylaxis, therapeutics, and vaccines for some of the world’s deadliest infectious diseases. Prior to co-founding Healion Bio, Dr. Bavari founded Edge BioInnovation Consulting and Mgt. and was the Chief Scientific Officer and Scientific Director at USAMRIID (US Army Research Institute of Infectious Diseases), where he spent over twenty years leading the discovery and development of vaccines, therapeutics, and diagnostics or diseases such as SARS and MERS CoVs, Ebola, Marburg, Zika, Smallpox, Sudan, Nipah, alpha viruses, Anthrax and many others. He has worked extensively with the FDA to successfully develop clinically proven countermeasures for many so-called envelope viruses like SARS-CoV-2. Dr. Bavari has contributed to ~20 drug development candidates such as Remdesivir, 30 patents, and many IND filings. He has trained over 70 scientists and managed over 500 scientists and supporting staff. His work has resulted in over 350 publications in many of the leading scientific journals including Nature, Nature Medicine, Cell, Cell Hosts, New England Journal of Medicine and many others. He has degrees from USC, and the University of Nebraska where he received his PhD in Immunotoxicology and Pharmaceutical Science.

Therapeutics Pipeline for COVID-19

Get the latest updates, interviews and receive special offers

Pre-register Today!

Ralph Rogers, MD

Assistant Professor of Medicine, Clinician Educator, Infectious Diseases, Warren Alpert Medical School of Brown University

Ralph Rogers, MD is an infectious disease specialist at the Lifespan Cancer Institute. He earned his medical degree from The Warren Alpert Medical School of Brown University where he also completed his residency and fellowship in infectious diseases. Dr. Rogers is Assistant Professor of Medicine, Clinician Educator Division of Infectious Diseases Warren Alpert Medical School of Brown University. He is a member of the Infectious Diseases Society of America (IDSA), the American Society for Microbiology (ASM) and the American Society of Transplantation (AST).

John Sninsky, PhD

Consultant, Translational Sciences

John J. Sninsky, PhD is a translational medicine consultant with deep understanding of diagnostics and diagnostics paired with medicine intervention. John has served in senior management positions in small and large CLIA service laboratories and in vitro diagnostic kit companies including Cetus, Roche Molecular Systems, Celera, Quest and CareDx. He was a member of the pioneering Cetus team that developed and optimized PCR technology for research and diagnostic use; specifically, the virology team developed the HIV, HTLV, HPV, HCV and HBV PCR assays. John put in place a surveillance initiative for viral variants and presented at the first FDA PMA advisory meeting for HIV PCR approval.

Timothy J. O’Leary, MD, PhD

Adjunct Professor, Pathology, University of Maryland School of Medicine; Former Chief Research and Development Officer, Veterans Affairs

Timothy O’Leary, MD, is Adjunct Professor of Pathology at the University of Maryland and served as Chief Research and Development Officer (CRADO) of the Department of Veterans Affairs from 2013-2015. He holds a doctorate in physical chemistry from Stanford University and a medical degree from the University of Michigan.

He is certified in anatomic pathology by the American Board of Pathology and in molecular genetic pathology by the American Board of Pathology and the American Board of Medical Genetics. Prior to his VA service, O’Leary chaired the Department of Cellular Pathology and Genetics at the Armed Forces Institute of Pathology for more than 15 years. He joined VA in 2004 and served as Director of Biomedical Laboratory Research and Development, Director of Clinical Sciences Research and Development, and Deputy CRADO prior to his appointment as CRADO. O’Leary also served as a reserve member of the Public Health Service Commissioned Corps from 1979 to 2010, serving two tours on active duty. His research interests include genomics, proteomics, and ultrasensitive detection of biological toxins. He has served on numerous federal panels and advisory committees, including the Health and Human Services Clinical Laboratory Improvement Advisory Committee and the Food and Drug Administration Hematology and Devices Panel. O’Leary, the holder of four patents, has authored or co-authored more than 190 journal articles and numerous book chapters and technical reports. He is a past president of the Association for Molecular Pathology and served as editor-in-chief for the Journal of Molecular Diagnostics.