A Closer Look at the Approval of CRISPR/Cas9 Gene Therapy for Sickle Cell Disease

P.J. Brooks, PhD, and Jeanita Pritchett Clay, PhD
8 Min Read

Brooks is a rare diseases researcher. Pritchett Clay is a researcher and chemist, and advocate for diversity in STEM.

On Friday, the FDA approved two gene therapies to treat patients with sickle cell disease (SCD). One of the therapies, called exagamglogene autotemcel (Casgevy), is the first FDA-approved gene therapy utilizing CRISPR/Cas9, a type of genome editing technology. It was approved for individuals ages 12 years and older who have recurrent vaso-occlusive crises (VOCs). While not unexpected, this approval is a landmark event.

Casgevy Therapy: Mechanism and Effect

The approved CRISPR-Cas9 gene therapy involves isolating hematopoietic stem cells (HSCs) from SCD patients and using CRISPR-Cas9 gene editing to reactivate fetal hemoglobin (HbF) genes that are normally turned off in adults. Specifically, this approach involves reducing the expression of a gene called BCL11A, which acts to prevent expression of HbF. Because the HbF gene does not carry the sickle mutation, the HbF protein outcompetes the sickle forming hemoglobin (HbS), thereby reducing sickling. The NIH has long supported basic, translational, and clinical research to improve health outcomes for people with SCD. Indeed, the therapeutic approach underlying Casgevy was made possible by a large amount of basic research on the regulation of gene expression in HSCs as well as genetic epidemiologic studies on blood disorders.

As presented at the FDA advisory committee meeting, of the 31 patients evaluable in the clinical trial, 29 showed significant reductions in VOCs. Moreover, none of the patients receiving Casgevy experienced VOCs that resulted in hospitalization, whereas prior to the trial, SCD patients were averaging 2.7 hospitalizations/year.

These results supported the effectiveness of the therapy. The main issue raised by FDA staff for the committee’s consideration was the potential for “off target” gene editing. Cas9 is an enzyme that can create changes to gene sequences in DNA. In the case of SCD therapy, the change created has a therapeutic effect. However, the mechanism for targeting Cas9 within the genome is not perfect and can in some cases result in mutations in genes other than the intended target. It is hypothetically possible that such an “off-target editing” event could contribute to the development of leukemia. The sponsors presented an extensive analysis of the possible off-target effects of Casgevy. Ultimately, FDA determined that the therapy met the safety and effectiveness standards for approval.

However, the technology is still in its early stages, and its long-term safety and efficacy need to be thoroughly evaluated. The sponsors presented plans for rigorous testing and patient monitoring over the next 15 years to address these concerns.

A Historical Perspective

While this approval is a historic event, we must acknowledge the systemic inequities and historical discrimination that the African-American community as a whole, and individuals living with SCD and SCD carriers in particular, have experienced with regard to biomedical research and healthcare.

Given this history, it is perhaps fitting that the first FDA-approved CRISPR/Cas9 gene therapy will specifically benefit this community. However, advocacy groups, researchers, healthcare organizations, and policymakers must remain committed to the principles of fairness, and to ensuring equitable access to this therapy, as well as education and community outreach initiatives to promote a broad and lasting impact for this therapy. NIH is currently updating existing educational materials developed by The Democratizing Education for Sickle Cell Disease Gene Therapy Project, which seeks to increase transparency about the risks and benefits of the SCD gene therapy processes, empowering patients as they decide whether to pursue one-time genetic therapies.

A Global Perspective

The vast majority of people living with SCD live outside the U.S. Given the complexity of Casgevy’s gene editing technology, the dissemination of this gene editing therapy into Africa and other low- and middle-income countries is not realistic. One approach to this problem would be in vivo genome editing, which does not require the isolation and editing of HSCs. Key to this approach is developing technologies to deliver gene editors to HSCs in vivo, perhaps using lipid nanoparticles (LNPs) carrying messenger RNA encoding genome editors. This approach is currently used to deliver genome editors to the liver but needs to be targeted to HSCs.

Since this would essentially be an adaptation of the same basic technology underlying the COVID-19 vaccines that were distributed globally, such an approach would open the potential for genome editing technologies to treat people living with SCD in Africa. Ongoing research is focused on developing better ways to deliver genome editors to target cells and tissues throughout the body, including HSCs.

Implications for Other Diseases

SCD is one of thousands of monogenic human diseases (those caused by mutations in a single gene). Thankfully, the cause of monogenic diseases is well understood, as are possible treatments. The basic therapeutic approach is to get a working copy of the mutant gene into target cells.

One of the most attractive aspects of CRISPR-Cas9 based gene editing is that it is a modular platform, with the basic components being the editor, the delivery system, and the guide RNA that targets the editor within the genome. As such, basically the same approach used in Casgevy should be applicable to edit genes in HSCs to treat other blood or immune diseases, by only changing the sequence of the guide RNA. For in vivo gene editing, multiple different platforms might be required, each based on delivery systems targeted to specific cells or tissues.

The approval of Casgevy is a significant step towards the clinical implementation of genome editing, but also a significant step towards the establishment of genome editing as a therapeutic platform (or platforms) that can be applied to a large number of monogenic diseases.

Of course, however, we must closely monitor the risks associated with CRISPR/Cas9 gene therapies. The technology — as it applies to SCD as well as other monogenic diseases — is still in its early stages, and its long-term safety and efficacy need to be thoroughly evaluated through trial data assessment, patient monitoring, and careful consideration of appropriate patient populations. This technology holds great potential — let’s continue to move forward, but proceed with caution.

P.J. Brooks, PhD, is the deputy director of the National Center for Advancing Translational Sciences (NCATS) Division of Rare Diseases Research Innovation at the NIH. Jeanita Pritchett Clay, PhD, is the chief scientific diversity officer at NCATS.

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