CRISPR clinical trials: gene editing explained for patients

What is CRISPR-Cas9 and how does it edit a gene?

CRISPR-Cas9 is a two-component system: a single guide RNA (sgRNA) and an endonuclease called Cas9 protein. The system comes from the immune defence of prokaryotes against phage infections and foreign substances^[1]. In a therapeutic setting, a guide RNA leads the Cas9 enzyme to a targeted DNA sequence, which is then edited for the desired change^[2].

The technology was developed by Emmanuelle Charpentier and Jennifer Doudna, who received the Nobel Prize in Chemistry in 2020. Editing enables the correction of harmful base mutations or the disruption of disease-causing genes^[1]. This differs from older gene therapy approaches that add functional copies of modified genes rather than editing existing sequences^[2].

Where does CRISPR fit among advanced therapy medicines?

In the European Union, advanced therapy medicinal products (ATMPs) are medicines for human use based on genes, tissues or cells. ATMPs are classified into three main types: gene therapy medicines, somatic-cell therapy medicines and tissue-engineered medicines. Gene therapy medicines contain genes that produce a therapeutic, prophylactic or diagnostic effect, inserted to treat genetic disorders, cancer or long-term diseases. Some ATMPs contain one or more medical devices as an integral part of the medicine and are called combined ATMPs^[3].

The European Medicines Agency (EMA) publishes scientific guidelines on gene therapy to help developers prepare marketing authorisation applications. These cover quality, non-clinical and clinical issues for recombinant adeno-associated viral vectors, management of clinical risks from insertional mutagenesis, and requirements for investigational ATMPs in clinical trials. Guidelines also address follow-up of patients administered with gene therapy medicinal products^[4].

Which CRISPR medicine is already authorised in the EU?

Casgevy (exagamglogene autotemcel) is authorised in the European Union for beta thalassaemia and sickle cell disease in patients aged 12 years and older. In beta thalassaemia it is used in patients who require regular blood transfusions; in sickle cell disease, in patients with severe disease and recurrent painful crises. Both conditions are rare, and Casgevy received orphan medicine designations – for beta thalassaemia on 17 October 2019 and for sickle cell disease on 9 January 2020^[5].

Casgevy contains genetically modified stem cells taken from the patient's own blood. It is used when stem cell treatments are appropriate and no suitable stem cell donors are available^[5]. For comparison, in the United States the same therapy was also under review, with the first approval decision for a CRISPR gene therapy expected during 2023^[2].

How is a CRISPR medicine made for one patient?

Casgevy is made individually for each patient from stem cells collected from their blood, and it must only be given to the patient for whom it is made. During manufacturing, the stem cells are edited using CRISPR/Cas9 technology so that they produce more fetal haemoglobin, a type of haemoglobin mainly found in babies in the womb and present in small amounts in adults. Fetal haemoglobin can compensate for the lack of normal adult haemoglobin^[5].

The edited cells are given as a single dose infusion into a vein, and the dose depends on the patient's bodyweight. Before the infusion, the patient receives conditioning chemotherapy to clear the bone marrow of cells. Casgevy can only be obtained with a prescription and must be given in an approved centre by a doctor trained in giving this medicine, with experience in stem cell transplantation and in treating blood disorders affecting haemoglobin^[5].

A related strategy also reactivates fetal haemoglobin to compensate for the lack of haemoglobin in beta thalassaemia or the defective haemoglobin in sickle cell disease. An alternative research approach replaces one of the alpha-globin genes with a healthy full-length beta-globin gene in a single CRISPR edit. This edit is performed in patient-derived haematopoietic cells outside the body, and the cells are then transfused into mice to monitor long-term reconstitution. A plug-and-play transgene knock-in platform has been developed to express clinically relevant proteins from cells of the erythroid lineage, under the control of the alpha-globin promoter, integrating different transgenes into human haematopoietic stem and progenitor cells^[6].

What results have been reported in CRISPR studies?

The effects of Casgevy are based on interim results of two studies that are still ongoing, and the studies did not compare the medicine to another medicine or placebo. In one study in patients with thalassaemia aged between 12 and 35 years, the medicine was given after conditioning chemotherapy. In that study, 39 of 42 patients maintained haemoglobin levels above 9 g/dL without the need for blood transfusions for at least 12 consecutive months^[5].

In a study in patients with severe sickle cell disease aged between 12 and 35 years, 28 of 29 patients did not experience any painful crises for at least 12 consecutive months when treated with Casgevy after conditioning chemotherapy. None of the 29 patients required hospitalisation for painful crises for at least 12 consecutive months^[5].

Results from the Phase II/III CLIMB SCD-121 trial in sickle cell disease were presented at the 2022 Annual Meeting of the American Society of Hematology, alongside other advanced CRISPR-based treatments for blood disorders. According to one expert cited at the time, exa-cel's clinical success represented a landmark, given that reactivating a mainly suppressed gene appeared to result in a cure or near cure^[2].

What risks and side effects are known?

The most common side effects with Casgevy, which may affect more than 1 in 10 people, include headache, nausea and muscle and bone pain. Doctors should consider whether patients can be given the required pre-treatments needed before Casgevy. For the full list of side effects and restrictions, the package leaflet should be consulted^[5].

Beyond authorised products, critical challenges for CRISPR-Cas9 include off-target effects, immune responses and the ethical considerations of germline editing. Off-target effects and delivery challenges persist across therapeutic applications^[1]. Historically, gene editing approaches were hampered by inaccurate and high rates of off-site lesioning and by overall low digestion rates, limitations that CRISPR/Cas9 may address^[7].

Research addressing efficiency has shown that a dysfunctional guide RNA can sometimes be salvaged rather than replaced; the guide has two components that must work together – an RNA sequence that recognises the DNA target site and a scaffolding sequence that holds the enzyme in place to cleave the DNA. Multiple RNA sequences were found to revive the integrity of the scaffolding, which the authors present as a step towards safer and more effective application of CRISPR technology as a therapy^[8].

Which parts of the genome are hard to edit?

There are many places within the human genome that cannot be edited well. In many cases the guide RNA may not fold exactly right or is otherwise corrupted, so the editing or deletion process cannot occur, and typically the guide must be swapped out for a new one. A research team used large libraries of different CRISPR RNAs together with informatics to reach more locations in the genome for repair. The researchers reported making hundreds of thousands of guide RNAs, which they describe as showing that the process is more adaptable than previously believed^[8].

For retinal disease, the ideal gene therapy approach would correct gene mutations to restore normal function in affected cells, which involves site-specific digestion of mutant genomic DNA followed by repair. In adult humans, gene therapy is considered more acceptable than editing human zygotes and embryos, but editing in adult eyes poses technical problems because development has already occurred and cells in the retina are terminally differentiated. Gene therapy in the human eye has progressed faster than in many other tissues because it does not require systemic delivery and dilution of therapeutic constructs; agents can be delivered directly by intravitreal or subretinal injection. Cultural and social understanding and acceptance of genetic editing varies greatly, and concern about editing genomes in human zygotes and embryos has led some countries to ban it^[7].

Which diseases are being studied in CRISPR clinical trials?

CRISPR-based blood cell therapies are advancing through clinical trials, with results reported for certain rare genetic diseases and some cancers. Beta thalassaemia is one of the most common rare genetic diseases and arises through any of more than 200 loss-of-function mutations in the beta-globin gene (HBB), which encodes one of the two building blocks in haemoglobin. HBB mutations result in a shortage of mature and functional adult haemoglobin, leading to symptoms ranging from mild to severe anaemia and early mortality, depending on the exact mutations present. Current treatments are limited to disease management, and long-term prognosis is poor^[6].

Approximately 7,000 distinct rare genetic diseases affect around 300 million people globally. One research goal is a one-size-fits-all genetic solution for a group of diseases that share the lack of expression of a specific protein in the blood; the specific protein varies from disease to disease, but most can be treated in the same way by injecting the missing protein into the blood^[6]. Over the past decade, research into CRISPR-Cas9 treatment of acquired diseases, including cancers, haemolytic and cardiovascular diseases, immunodeficiency and visual or neurodegenerative disorders, has expanded significantly with positive outcomes^[1]. CRISPR gene editing has been used to treat diseases such as sickle cell anaemia, leukaemia and genetic disorders, but challenges limit its broad utility^[8].

How do you recognise an unregulated advanced therapy?

Unregulated advanced therapies may put patients at risk of serious side effects without any proven benefits, and they are often sold on websites or through social media as a last hope, exploiting the worries of patients and their families. Authorities are clamping down on those supplying unregulated ATMPs and encourage patients and caregivers to report suspicious cases to their national authorities^[3].

Warning signs include a provider marketing the product as experimental but using it outside an authorised clinical trial, a provider unable to confirm that the product has been approved by the EMA or for use by a national authority, and claims of benefits exceeding those of approved treatments without supporting medical literature. If you or a family member has been offered an advanced therapy, you can contact your national competent authority to verify its approval, and you should be cautious with treatments promoted online or through social media, always seeking a second opinion before proceeding^[3].

The EMA's Committee for Advanced Therapies and the Heads of Medicines Agencies released a statement on the risks of unregulated advanced therapies in March 2025, following reports of providers offering unregulated dendritic cell therapies for cancer treatment in the EU. The statement covers practical advice for patients and caregivers on how to identify unregulated advanced therapies. A similar statement was issued by the Committee in April 2020^[3].

What should you ask before consenting to a gene editing trial?

Ask which phase the study is in and whether it has a comparison group, because the studies supporting the authorised CRISPR medicine for blood disorders did not compare it to another medicine or placebo. Ask whether conditioning chemotherapy is required before the edited cells are given, since this step clears the bone marrow and is part of the treatment pathway^[5]. Ask about the follow-up schedule: EMA guidelines specifically address follow-up of patients administered with gene therapy medicinal products and safety and efficacy follow-up with risk management^[4].

Ask where the treatment must be given, because a CRISPR medicine given by infusion is administered in an approved centre by a doctor trained in the procedure and experienced in stem cell transplantation. Ask for the package leaflet and the full list of side effects and restrictions before deciding^[5].

How can you find a CRISPR clinical trial in Europe?

Studies of medicines in the EU are listed in European registries, and the same studies are also published in public trial databases so that patients and caregivers can look for studies by disease and location. Trials recruiting in Europe can also be searched on clinicaltrials.eu. Ask your treating physician whether a trial is open for your condition and whether you meet its criteria, because eligibility depends on the specific study protocol.

When to consult your doctor or pharmacist

Speak to your treating physician before agreeing to any gene editing treatment or trial, and ask whether your condition and prior treatments match the study population, such as the age range of 12 to 35 years used in the blood disorder studies^[5]. If you have been offered an advanced therapy outside an authorised clinical trial, contact your national competent authority to verify its approval before proceeding^[3]. Report any side effect of an authorised medicine to your doctor, who can advise on the next steps and on the full list of side effects and restrictions in the package leaflet^[5].

Summary

CRISPR-Cas9 combines a guide RNA with the Cas9 enzyme to cut and repair a specific DNA sequence, which distinguishes it from gene therapies that add functional gene copies^[2]. One CRISPR medicine is authorised in the EU for beta thalassaemia and sickle cell disease, and it is manufactured individually from each patient's own stem cells, given as a single infusion after conditioning chemotherapy^[5].

Before joining any gene editing trial, confirm the study phase, whether a comparison group exists, whether conditioning chemotherapy is part of the protocol, the follow-up schedule and the centre where the infusion will be given. Check that the therapy is authorised or being used inside an authorised clinical trial, and verify any offer with your national competent authority if it comes from a website or social media.

1. [1] European Journal of Translational and Clinical Medicine — ejtcm.gumed.edu.pl (accessed 06.10.2026) — https://ejtcm.gumed.edu.pl/articles/215857
2. [2] Zamecnik A. CRISPR gene therapies: Is 2023 a milestone year in the making? Pharma Technology Focus. February 2023 (accessed 2 June 2026) — https://pharma.nridigital.com/pharma_feb23/crispr-gene-therapies-is-2023-a-milestone-year-in-the-making
3. [3] Advanced therapy medicinal products: Overview | European Medicines Agency (EMA) (accessed 2 June 2026) — https://www.ema.europa.eu/en/human-regulatory-overview/advanced-therapy-medicinal-products-overview
4. [4] Multidisciplinary guidelines: gene therapy | European Medicines Agency (EMA) (accessed 2 June 2026) — https://www.ema.europa.eu/en/human-regulatory-overview/research-development/scientific-guidelines/multidisciplinary-guidelines/multidisciplinary-gene-therapy
5. [5] Casgevy | European Medicines Agency (EMA) (accessed 2 June 2026) — https://www.ema.europa.eu/en/medicines/human/EPAR/casgevy
6. [6] Interview Roundup: CRISPR Approaches To Curing Rare Diseases | CRISPR Medicine (accessed 2 June 2026) — https://crisprmedicinenews.com/news/interview-roundup-crispr-approaches-to-curing-rare-diseases/
7. [7] CRISPR challenges in treating retinal disease - PMC — PubMed Central (accessed 06.10.2026) — https://pmc.ncbi.nlm.nih.gov/articles/PMC4975549/
8. [8] Improvement to CRISPR Gene Editing Could Make It More Effective | Duke Cancer Institute (accessed 2 June 2026) — https://www.dukecancerinstitute.org/blogs/improvement-crispr-gene-editing-could-make-it-more-effective