World First: CRISPR Gene Editing Approved in the UK

Introduction

The UK Medicines and Healthcare products Regulatory Agency (MHRA) granted conditional marketing approval for Vertex & CRISPR Therapeutics' Casgevy to treat Sickle Cell Disease (SCD) and transfusion-dependent beta thalassemia on November 16, 2023. [Pai, 2023]

The day before the announcement:

- CRISPR Therapeutics AG (CRSP) was trading at $56.23.

- Vertex Pharmaceuticals Inc (VRTX) was trading at $349.34

The day after the announcement:

- CRISPR Therapeutics AG (CRSP) closed at $67.89 on November 17, 2023, which is an increase of approximately 20.74%.

- Vertex Pharmaceuticals Inc (VRTX) closed at $350.50 on November 17, 2023, which is an increase of approximately 0.33%.

Casgevy is a genetically modified autologous CD34+ cell enriched population, featuring human hematopoietic stem and progenitor cells that have undergone ex vivo editing by CRISPR/Cas9. This editing specifically targets the erythroid-specific enhancer region of the BCL11A gene.

What the Data Say

In two global clinical trials of CASGEVY (Genetically Modified Autologous CD34+ Cell Enriched Population) in Sickle Cell Disease (SCD) and Transfusion-Dependent Thalassemia (TDT), specifically, CLIMB-111 and CLIMB-121, the trials successfully achieved their respective primary outcomes. Participants became free from severe Vaso-Occlusive Crises (VOCs) or achieved transfusion independence for at least 12 consecutive months. Once these benefits are realized, they are anticipated to provide potential life-long advantages.

The safety profile observed in 97 SCD and TDT patients treated with CASGEVY in these ongoing studies was generally equivalent to the safety considerations associated with myeloablative conditioning using busulfan and hematopoietic stem cell transplant.

Casgevy is currently undergoing additional evaluations by the European Medicines Agency, the Saudi Food and Drug Authority, and the U.S. Food and Drug Administration (FDA). For Sickle Cell Disease (SCD), the FDA has accorded Priority Review, while for Transfusion-Dependent Thalassemia (TDT), a Standard Review is in progress.

The Potential of Gene Editing

Gene editing has the potential to correct rare genetic diseases, such as SCD and Thalassemia prompting the development of several technologies to achieve this including Transcription Activator-Like Effector Nuclease (TALEN) and Zinc Finger Nuclease (ZFN), but none had achieved market approval until now. [Zhu, 2022] Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) gene editing technology has certain usability advantages that helped it win conditional regulatory approval in the UK, a world first for the technology. [Le Page, 2021] [Tong, 2023] CRISPR was not invented, rather it was found naturally occurring in some bacteria and most archaea (the third domain of life) and then later modified for use as biotechnology. [Ishino, 1987] [Jinek, 2012]

CRISPR in the Wild

CRISPR systems consist of an operon of CRISPR-associated (cas) genes and a CRISPR array. This array is made up of a leader sequence followed by a series of short, identical direct repeats (DRs) interspaced by unique spacer sequences. [Jinek, 2012] The spacers originate from mobile genetic elements, which were memorized upon an initial infection with phage or archaeal viruses. In turn, they enable the recognition of invading viral elements during subsequent infections. Thus, CRISPR is a type of prokaryotic adaptive immune system.

Classification of CRISPR Systems

There are two classes and five types of CRISPR/Cas systems. [Makarova, 2015] Precursor CRISPR RNAs (pre-crRNAs) are formed after the transcription of the CRISPR locus. Each type of system exhibits distinct characteristics in its mechanisms of pre-crRNA processing and differ in their roles in recognizing and cleaving nucleic acids. [Charpentier, 2015]

Class I - Multisubunit Effector Complexes

Type I, III, and IV systems have common features including specialized Cas endonucleases that process the pre-crRNAs. Each crRNA matures and combines into a large multi-Cas protein complex. The Cas complex is capable of recognizing and cleaving nucleic acids complementary to the crRNA.

Class II - Single Protein Multidomain Effector Complexes

Type II and putative type V systems have a unique mechanism that processes pre-crRNAs differently from class I systems. A pre-crRNA is transcribed from the CRISPR locus. Processing of pre-crRNAs involves double-stranded (ds) RNA-specific ribonuclease RNase III and occurs in the presence of Cas9. The processed crRNA then base-pairs to a trans-activating crRNA (tracrRNA) via the DR sequences to form a dual-RNA structure that guides Cas9 to make double-stranded (ds) breaks in target DNA. [Jinek, 2012], In type II systems Cas9 is believed to be the sole protein responsible for silencing foreign viral DNA.

Casgevy CRISPR

The CRISPR system used in Casgevy is a type II (Cas9) and was derived from the work of Emmanuelle Charpentier on the pathogenic bacterium Streptococcus pyogenes. [Le Rhun, 2019] Charpentier and Jennifer Doudna shared the 2020 Nobel Prize in Chemistry for developing the CRISPR/Cas9 technology. [Fernholm, 2020] CRISPR Therapeutics was co-founded by Charpentier and others to bring the technology to market. [Who, 2023]

The innovation of a single-guide RNA (sgRNA) for the Cas9 CRISPR biotechnological system by Charpentier's research group was a significant breakthrough in the field of genome editing. [Jinek, 2012] This synthetic sgRNA contains both the crRNA and tracrRNA sequences, and as a result, the technology is independent of RNAse III.

The sgRNA sequence directs Cas9 to the target site and can be modified to direct DNA cutting to any desired sequence/ gene. The gRNAs can be engineered to improve the CRISPR system's overall stability, specificity, safety, and versatility, such as fluorescent labeling. [Allen, 2020]

Guide RNAs have been modified to increase their stability to guard against nuclease degradation. Specificity has been improved by limiting off-target editing. Synthetic gRNA has been shown to ameliorate inflammatory signaling caused by the CRISPR system, thereby limiting immunogenicity and toxicity in edited mammalian cells. [Allen, 2020]

In summary, Charpentier's innovation of gRNA for the Cas9 CRISPR system has revolutionized the field of gene therapy and genome editing, providing a versatile and efficient tool for precise genetic modifications.

Casgevy Therapy for Sickle Cell and Thalassemia

The treatment procedure involves the following steps: [Canver, 2016]

1) Extraction of Stem Cells: Doctors take stem cells from the patient's bone marrow.

2) Chemotherapy: Patients first receive a course of chemotherapy to make space for the new cells.

3) Gene Editing: The extracted CD34+ stem cells are then taken to a laboratory where the BCL11A gene is silenced by Casgevy. This enables the body to create properly functioning fetal hemoglobin.

4) Reinfusion: The genetically edited cells are then infused back into the patient.

This treatment is intended to permanently correct for the underlying mechanism of these diseases. [Pai, 2023]

Conclusion

The financial markets responded positively to the conditional marketing approval granted by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for Casgevy, a groundbreaking treatment for Sickle Cell Disease (SCD) and transfusion-dependent beta thalassemia.

Casgevy represents a significant stride forward in the regulation of gene editing, obtaining conditional approval as a genetically modified autologous CD34+ cell enriched population that undergoes ex vivo editing through the CRISPR/Cas9 technology. This transformative approach holds immense promise for rectifying rare genetic disorders such as SCD and Thalassemia.

Casgevy is under ongoing investigation by the regulatory bodies including the European Medicines Agency, the Saudi Food and Drug Authority, and the U.S. Food and Drug Administration (FDA), the potential for additional approvals and expanded usage of this innovative treatment becomes increasingly apparent.

Delving into the intricacies of CRISPR systems, including their classification and functioning, reveals the complexity and vast potential of this cutting-edge technology in the ever-evolving landscape of gene editing.

REFERENCES

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Canver, Matthew C., and Stuart H. Orkin. "Customizing the Genome as Therapy for the β-Hemoglobinopathies." Blood, vol. 127, no. 21, 2016, pp. 2536-2545, https://doi.org/10.1182/blood-2016-01-678128.

Charpentier, Emmanuelle et al. "Biogenesis pathways of RNA guides in archaeal and bacterial CRISPR-Cas adaptive immunity." FEMS Microbiology Reviews, vol. 39, no. 3, 2015, pp. 428-441. doi: 10.1093/femsre/fuv023.

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Le Page, Michael. "What Is CRISPR?" New Scientist, New Scientist Ltd., 26 Mar. 2021, www.newscientist.com/definition/what-is-crispr/.

Le Rhun, A., Escalera-Maurer, A., Bratovi?, M., Charpentier, E. "CRISPR-Cas in Streptococcus pyogenes." RNA Biology, vol. 16, no. 4, 2019, pp. 380-389. https://doi.org/10.1080/15476286.2019.1582974.

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Pai, Manisha, et al. "Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVYTM (Exagamglogene Autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia." Business Wire, Vertex Pharmaceuticals Incorporated & CRISPR Therapeutics, 16 Nov. 2023, www.businesswire.com/news/home/20231115290500/en/.

Tong, Amber, and Lei Lei Wu. "In a World First, Vertex, CRISPR Win UK Approval for CRISPR-Edited Therapy to Treat Sickle Cell Disease, Beta-Thalassemia." Endpoints News, Endpoints News, 16 Nov. 2023, endpts.com/uk-approves-vertex-crispr-therapy-for-sickle-cell-disease-beta-thalassemia-in-world-first/.

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Zhu, Guoning, and Hongliang Zhu. "Modified Gene Editing Systems: Diverse Bioengineering Tools and Crop Improvement." Frontiers in Plant Science, vol. 13, 2022, article 847169. doi: 10.3389/fpls.2022.847169.

About The Author

David  Orchard-Webb, Ph.D., is a technical writer with broad interests including  health & technology writing, plus extensive training and knowledge of  biomedicine and microbiology. My Ph.D. and postdoc were in oncology and  developing cancer medicines. I provide technical medical and other writing  services for projects ranging from “knowledge automation” to pure pharma, to  food safety, to the history of science, and everything in between. I also  provide white papers, ebooks, meta-analysis reviews, editing, consulting,  business, and market research-related activities in biomedicine, technology,  and health. In addition to its well-known role in the development of  medicines, I am a big believer in biotechnology’s ability to revolutionize  industries such as food-tech, agtech, textiles & fashion.