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Gene editing-based therapies could revolutionize how genetic diseases are treated

Published March 7th, 2024

Patients with the debilitating, inherited blood disorders sickle cell anemia and beta-thalassemia recently received news of a life-changing treatment. The FDA approved Casgevy, a groundbreaking therapy that uses a gene editing tool called CRISPR (pronounced ‘crisper’) to treat these disorders. This is the first ever approval for this innovative type of treatment, which can change the DNA code in a patient’s cells to target the underlying cause of a disease. The approval was widely celebrated because CRISPR-based treatments have the potential to completely change how genetic diseases are treated.

Gene editing with CRISPR-Cas9
Treating or curing disease with gene editing has been a goal for decades, but initial efforts using gene therapy in the 1990s through the 2000s had minimal success.1,2 However, in 2012, the gene-editing potential of a system called CRISPR-Cas9 was demonstrated. This system gave researchers the ability to edit DNA quickly, easily, and accurately,3,4 which ushered in a flurry of possibilities for new therapies for inherited disorders and cancer. Indeed, the potential for CRISPR-Cas9 gene editing is so high its discoverers were awarded the 2020 Nobel Prize in Chemistry.

As a gene editing tool, CRISPR-Cas9 is like a precise molecular scissor that allows researchers to cut and paste DNA sequences into the genome. In this way, researchers can change DNA by introducing or removing mutations. The CRISPR-Cas9 gene editing system works by repurposing a naturally occurring mechanism that bacteria use to fight viral infections.5 Specifically, the technology uses two molecules from the bacterial “immune system.” The first molecule, CRISPR, “reads” DNA sequences and guides the second molecule, Cas9, to cut that exact DNA sequence. Then, when the cell begins to repair the cut DNA, new, edited DNA can be introduced.




Newly approved CRISPR-based treatment for blood disorders
Sickle cell disease and a similar condition called beta-thalassemia are caused by inherited mutations in a gene involved in making the adult hemoglobin protein, which transports oxygen through the bloodstream. The mutations result in abnormally shaped red blood cells, which cause anemia, severe pain, and other debilitating symptoms. Casgevy takes advantage of a special trait in human development to treat these diseases.

Humans make two types of hemoglobin, fetal and adult. While in the womb, humans make the fetal version because it allows the fetus to efficiently absorb oxygen through the placenta. Shortly after birth, the fetal hemoglobin gene is shut “off”, and the adult hemoglobin gene is turned “on”. But there are known mutations that allow the fetal hemoglobin gene to remain “on” even after birth,6 and CRISPR-based treatment exploits this. In the clinical trials that led to the approval of Casgevy, it was shown that if a patient’s blood stem cells were extracted, edited with CRISPR to switch “on” the fetal hemoglobin gene, and given back to the patient, normal blood cells develop and sickle cell disease could be corrected.7,8 Researchers expect that a single round of Casgevy treatment will last for many years and possibly for the patient’s lifetime.

Potential for CRISPR-based cancer therapies
Cancer occurs when mutations cause a person’s own cells to grow out of control. As such, there are many potential applications for CRISPR, which include editing out mutations that drive tumor growth, preventing drug resistance, modifying immune cells to help kill tumor cells, and more.9-11

The most promising early results for CRISPR-based therapies in cancer involve collecting a patient’s immune cells and editing them, so they can attack cancer more efficiently.12 Many clinical trials are now underway that seek to edit immune cells using CRISPR to enhance their cancer-killing potential. These include various cancer types, such as lymphoma, leukemia, multiple myeloma, esophageal, and other solid tumors.13-16

Future prospects and challenges
For now, CRISPR-based treatment involves editing cells outside the body and returning the cells to the patient, but one major ambition of the technology is to correct disease-causing mutations inside a patient’s body. This could open the door to curing or preventing diseases such as muscular dystrophy, familial hypercholesterolemia, Alzheimer’s, Huntington’s disease, Lou Gehrig’s disease, cancer predisposition, and many others.17,18

There are challenges involved in doing this. For example, CRISPR-Cas9 must be delivered to the correct location (liver, brain, muscles, etc.) and must avoid being destroyed by the immune system. It must also be shown that delivering CRISPR-Cas9 to the body is safe over the long term. If it enters the wrong cells or accidentally edits the wrong gene, it could have serious consequences, including autoimmune disease, new cancers, fertility issues, dangerous inflammation, or other health problems.19,20

At PHM, we are excited about the potential of CRIPSR while staying cognizant of the challenges. We assess each new application and the corresponding clinical trials to determine whether our patients with serious and complex diagnoses could benefit.

References

  1. Raper, S. E. et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 80, 148-158, doi:10.1016/j.ymgme.2003.08.016 (2003).
  2. Ram, Z. et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vector-producing cells. Nat Med 3, 1354-1361, doi:10.1038/nm1297-1354 (1997).
  3. Jinek, M. et al. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337, 816-821, doi:10.1126/science.1225829 (2012).
  4. Cong, L. et al. Multiplex genome engineering using CRISPR/Cas systems. Science 339, 819-823, doi:10.1126/science.1231143 (2013).
  5. Bhaya, D., Davison, M. & Barrangou, R. CRISPR-Cas systems in bacteria and archaea: versatile small RNAs for adaptive defense and regulation. Annu Rev Genet 45, 273-297, doi:10.1146/annurev-genet-110410-132430 (2011).
  6. Sankaran, V. G. & Orkin, S. H. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 3, a011643, doi:10.1101/cshperspect.a011643 (2013).
  7. Frangoul, H. et al. CRISPR-Cas9 Gene Editing for Sickle Cell Disease and beta-Thalassemia. N Engl J Med 384, 252-260, doi:10.1056/NEJMoa2031054 (2021).
  8. Frangoul, H. et al. Exagamglogene Autotemcel for Severe Sickle Cell Disease. Blood 142, 1052-1052, doi:10.1182/blood-2023-190139 (2023).
  9. Koo, T. et al. Selective disruption of an oncogenic mutant allele by CRISPR/Cas9 induces efficient tumor regression. Nucleic Acids Res 45, 7897-7908, doi:10.1093/nar/gkx490 (2017).
  10. Chehelgerdi, M. et al. Comprehensive review of CRISPR-based gene editing: mechanisms, challenges, and applications in cancer therapy. Mol Cancer 23, 9, doi:10.1186/s12943-023-01925-5 (2024).
  11. Katti, A., Diaz, B. J., Caragine, C. M., Sanjana, N. E. & Dow, L. E. CRISPR in cancer biology and therapy. Nat Rev Cancer 22, 259-279, doi:10.1038/s41568-022-00441-w (2022).
  12. Stadtmauer, E. A. et al. CRISPR-engineered T cells in patients with refractory cancer. Science 367, doi:10.1126/science.aba7365 (2020).
  13. Benjamin, R. et al. UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial. Lancet Haematol 9, e833-e843, doi:10.1016/S2352-3026(22)00245-9 (2022).
  14. Chen, S. & Lin, Y. Phase I clinical trial using a unique immunotherapeutic combination of MUC1-targeted CAR-T cells with PD-1-knockout in the treatment of patients with advanced esophageal cancer. Journal of Clinical Oncology 41, e16061-e16061, doi:10.1200/JCO.2023.41.16_suppl.e16061 (2023).
  15. Wang, Z. et al. Phase I study of CAR-T cells with PD-1 and TCR disruption in mesothelin-positive solid tumors. Cell Mol Immunol 18, 2188-2198, doi:10.1038/s41423-021-00749-x (2021).
  16. Hu, Y. et al. CRISPR/Cas9-Engineered Universal CD19/CD22 Dual-Targeted CAR-T Cell Therapy for Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res 27, 2764-2772, doi:10.1158/1078-0432.CCR-20-3863 (2021).
  17. Behr, M., Zhou, J., Xu, B. & Zhang, H. In vivo delivery of CRISPR-Cas9 therapeutics: Progress and challenges. Acta Pharm Sin B 11, 2150-2171, doi:10.1016/j.apsb.2021.05.020 (2021).
  18. Stefanoudakis, D. et al. The Potential Revolution of Cancer Treatment with CRISPR Technology. Cancers (Basel) 15, doi:10.3390/cancers15061813 (2023).
  19. Zheng, N., Li, L. & Wang, X. Molecular mechanisms, off-target activities, and clinical potentials of genome editing systems. Clin Transl Med 10, 412-426, doi:10.1002/ctm2.34 (2020).
  20. Newman, A., Starrs, L. & Burgio, G. Cas9 Cuts and Consequences; Detecting, Predicting, and Mitigating CRISPR/Cas9 On- and Off-Target Damage: Techniques for Detecting, Predicting, and Mitigating the On- and off-target Effects of Cas9 Editing. Bioessays 42, e2000047, doi:10.1002/bies.202000047 (2020).

About the Author

Ross Keller, PhD

Research Director

Dr. Keller is focused on providing decision-grade information to cancer patients regarding the best treatments options. He has experience in genomics, cancer evolution, tumor modeling, and early-stage drug development.