TABLE OF CONTENTS

CRISPR Gene Editing: A Revolutionary Approach to Treating Sickle Cell Disease

Tags: crispr cas9

Introduction

Sickle cell disease is common worldwide, primarily in Africa, the Mediterranean and the Middle East. A quarter of a million people worldwide are affected by the condition. The disease has a dramatic effect on patients' lives, including frequent medical treatment, low quality of life and diminished life expectancy.

The conventional treatments mostly involve drugs and stem cell transplantation. Medications, like hydroxyurea, can alleviate symptoms and lower the risk of acute events, but do not prevent the disease. Stem cell transplantation is the only cure for sickle cell disease, but its effectiveness hinges on donors, and it involves graft-versus-host disease. Moreover, stem cell transplants are expensive and hard to promote in most low-income economies.

The CRISPR gene editing technology has given sickle cell disease a new lease of life in recent years. CRISPR/Cas9 can locate and modify DNA sequences to repair or replace mutant genes that promote sickle cell disease. CRISPR can, for instance, reactivate the -globin gene and reinstate normal red blood cell activity. CRISPR can also be used to generate induced pluripotent stem cells (iPSCs) that can be converted into healthy hematopoietic stem cells for transplantation. Discover the comprehensive CRISPR/Cas9 knockout libraries offered by CD Biosynsis for your gene editing needs.

Traditional therapies focus on drug treatment and stem cell transplantation. Healthcare interventions like hydroxyurea are helpful in alleviating symptoms and reducing acute events, but they do not eradicate the condition. Currently, the only possible cure for sickle cell disease is stem cell transplantation, but its effectiveness depends on donor availability and has risks like graft-versus-host disease. Moreover, stem cell transplants are costly and not easily disseminated in most low-income economies.

Since then, CRISPR gene editing has brought new promise to sickle cell disease. The CRISPR/Cas9 technology can identify and edit DNA sequences to repair or substitute for mutant genes that contribute to sickle cell disease. CRISPR technology, for instance, can normalise the expression of the -globin gene and normalise red blood cell function. Alternatively, CRISPR technology can be employed to create induced pluripotent stem cells (iPSCs) that can be transformed into healthy hematopoietic stem cells for transplantation.Explore the advanced CRISPR-based gene editing services provided by CD Biosynsis to enhance your research.

Schematic of clinical genome editing approaches for SCD.(Zarghamian,, et al.,2023)

While CRISPR technology is a winner in the lab, its use in clinical settings is in its infancy. More recently, CRISPR gene editing has been shown to be an effective means of correcting mutant genes in sickle cell disease and to deliver therapeutically useful results in animals. But the question of how to use this technology in a clinical therapy that is safe and effective remains unanswered, such as off-target effects, delivery systems optimization, and long-term safety.

CRISPR gene editing offers novel avenues for treating sickle cell disease, which may one day be entirely cured. But to do so is not an easy technical, moral or economic proposition.

Background on Sickle Cell Disease

Sickle Cell Disease (SCD) is a genetic condition in which mutations in the HBB gene interfere with the production of normal hemoglobin. Typically, hemoglobin is divided into four units, with two alpha-globulin units and two beta-globulin units. Those fragments combine to produce normal haemoglobin (HbA), which transports oxygen efficiently to tissues throughout the body.

However, in sickle cell disease, the HBB gene is mutated, swapping the sixth glutamic acid in the -globulin chain for valine (GAGGTG), and hemoglobin becomes abnormal (HbS). This deadly haemoglobin polymerises in hypoxia and causes red blood cells to become sickle-like and brittle. Blood clots that are not designed to carry oxygen normally can rapidly block blood vessels and cause enormous problems.

Sickle cell disease symptoms and complications vary, but typically involve severe anaemia, painful infections and organ failure. Anemia caused by an abnormal level of hemoglobin decreases the life span of red blood cells and reduces the capacity of the bone marrow to produce red blood cells. Chronic pain usually results from plugged blood vessels and can radiate to various parts of the body such as the abdomen, joints and muscles. Additionally, sickle cell patients can become prone to infection, particularly pneumonias, as infected red blood cells plug up small pulmonary blood vessels and prevent breathing.

Chronic sickle cell disease also robs the body of many of its organs – the kidneys, the liver, the heart, the eyes. Damage to kidneys can occur when capillary inflammation obstructs dysfunctional red blood cells. Additionally, retinal degeneration causes vision loss, sometimes blindness.

Complications of sickle cell disease and thromboinflammation(Conran, et al, 2020)

CRISPR for Sickle Cell Disease Treatment

CRISPR is currently used to treat Sickle Cell Disease (SCD) and to correct mutations in the beta-globin gene (HBB gene) that trigger the disease using gene editing software (mainly, CRISPR-Cas9). That approach will directly repair or replace the mutant gene that triggers sickle cell production, returning normal hemoglobin production and treating patients. Accelerate your drug development with CRISPR screening services from CD Biosynsis.

Overview of CRISPR Strategy for Sickle Cell Disease

Sickle cell disease – inherited, and driven by changes in the beta-globin gene (HBB gene) – makes red blood cells sickle-shaped, and it's complicated. The researchers can hack these mutant genes with CRISPR-Cas9, and delete the right DNA fragments. It's how CRISPR-Cas9 can repair or replace the mutated HBB gene, which will then normalise production of haemoglobin. CRISPR can also dampen symptoms by inducing foetal HbF production, which silences sickle red blood cells.

Genetic strategies for sickle cell diseas(Demirci, et al, 2018)

Research Preclinical and Early clinical trials.

Until now, CRISPR technology had proven safe and effective in animal models before it went into clinical trials. For instance, sickle-mutation fixes in human CD34 + hematopoietic stem cells have been achieved using CRISPR-Cas9, and the cells survive well in mice post-transplant and create normal haemoglobin. Then there are early human trials demonstrating success with treatments such as CTX001, a stem cell therapy based on autologous gene editing that can boost fetal haemoglobin levels significantly in clinical trials and avoid blood transfusions.

1. CTX001 test

CTX001, a CRISPR-Cas9 gene editing therapy for sickle cell disease and beta-thalassemia. The treatment switches patient's HSPCs to make adult-normal haemoglobin. In early clinical trials, CTX001 was effective. In one Phase 1/2 trial in severe sickle cell disease, for instance, CTX001 patients needed no blood transfusions for one year and suffered no major complications for two years.

2. CRISPR-Cas9 editing red blood cells research.

There's also an experiment looking at CRISPR-Cas9-edited red blood cell transplantation for sickle cell disease. This research – being done with UCLA and UCSF – will lead to a treatment that is both safe and affordable. It's already been shown that this approach is safe in pre-treatment and should turn out to be a useful treatment.

3. other trials

Other experiments are testing other forms of gene editing. Nula-cel, for instance, a therapy that switches the HbS gene with CRISPR-Cas9 technology to the HbA gene is in Phase 1/2 clinical trials. Then there is research that is looking at increasing foetal hemoglobin levels by inhibiting BCL11A activity via gene editing.

Even then, there are still hurdles and dangers with CRISPR treatment. Gene editing, for instance, can have off-target effects, where other genes get accidentally edited, leading to illness. Second, the problem of how to get gene editing tools on target cells.Build your custom CRISPR libraries with the CRISPR library construction services offered by CD Biosynsis.

Potential benefits of treatment

It's not only in the treatment of sickle cell disease that CRISPR could prove transformative. In the first place, it can cure the disease, not just the symptoms. Once genes are corrected, patients don't have to depend on blood transfusions and pain relief for the rest of their lives. Second, CRISPR treatment has been shown to enhance patients' 'quality of life' and decrease the adverse effects of the disease (crash of a vessel and organ destruction). Additionally, because a suitable donor isn't required, the treatment could also be new hope for patients who are unable to secure a bone marrow donor.

For sickle cell patients, CRISPR opens new treatment options like never before. Even if some technical and ethical issues are still pending, as research and technology develop further, this new form of treatment could be the next great revolution to treat this disease.

CRISPR for Sickle Cell Disease Treatment FDA Approval Process and Current Status

How the FDA would review a new gene therapy

Preclinical research: For this stage, the safety, dose and toxicology of gene therapy are the primary concerns. These are usually studies using animal models to determine whether gene editing methods are efficient or safe.
Clinical trial phase:
Phase I: mostly tests the safety and tolerability of gene therapy, usually in a limited number of patients.
Phase II: Increase efficacy and keep an eye on safety.
Phase III: Efficacy and safety testing at a scale of hundreds or thousands of patients.
Safety and Effectiveness Test: If the FDA has received sufficient safety and effectiveness data after all stages of the clinical trial, it may allow the product or therapy for marketing.

FDA approves CRISPR therapy process for sickle cells

In the case of CRISPR therapy for sickle cell, FDA has approved two CRISPR/Cas9 gene therapies-Casgevy and Lyfgenia. The two treatments are prescribed to sickle cell patients 12 and over. Casgevy is the first FDA-cleared CRISPR/Cas9 gene therapy.

The study of gene therapy for sickle cell is still in various phases of clinical trials. Others are for instance trying to use CRISPR/Cas9 to snip the BCL11A gene to increase foetal HbF and thus patients' symptoms.

CRISPR in clinical practice(Sonnaila, et al, 2024)

These treatments often take multiple clinical trial cycles before they're safely and effectively efficacious in the long term.

FDA issues with gene therapy

Safety over the long term: There could be significant long-term unknown risks in gene therapy, particularly if genome editing is used. This needs to be backed up by long-term follow-up studies to make treatment safe.
Consistency of manufacture: Gene therapies are complex and expensive to manufacture, so manufacturing the exact same product batch each time is a real challenge.
Ethics: Genetic engineering tools like CRISPR/Cas9 are ethically disputed, particularly in the case of editing human germ cells. So the creation of an integrated ethical and legal regulatory system is absolutely essential.

Nevertheless, gene therapy remains promising as a therapy for sickle cell disease, and as the technology develops and the regulatory environment changes, more patients will come to light.

Future Prospects and Implications

CRISPR gene editing is going to be used for sickle cell disease (SCD) in many ways. In the first place, if CRISPR is eventually commercialised and deployed to cure sickle cell disease, then it will have cost savings, patient outcomes, and potentially widespread use.

Profound application: CRISPR offers novel avenues for treating sickle cell by precisely correcting the genetic mutations that cause the disease. CRISPR/Cas9, for instance, has been used to show that editing the beta globin gene in hematopoietic stem cells can produce more hemoglobin and reduce the symptoms of sickle cell disease.

Moreover, in one instance, studies showed that stem cells repaired by CRISPR could be transplanted successfully into mice and thus can be clinically used in the future. Once the technology is complete and the cost is reduced, this treatment will likely be adopted in sickle cell patients one day.

Reduction of medical expenses: Existing treatment strategies like drug therapy, blood transfusions and bone marrow transplantation suffer from complications like lack of donors and high maintenance costs. Its cure comes from CRISPR technology which removes the cause once, in a way that means treatment will only be required once and it could save patients money in overall medical costs.

Improve outcomes: CRISPR technology is poised to revolutionise the lives of sickle cell patients. If you can repair the genetic mutation that leads to sickle cell, patients won't have to deal with pain, organ damage and other side effects of the disease. Furthermore, there have been cases in which patients' hemoglobin levels have improved following gene-engineered stem cell transplantation, and their lives have become significantly better. Ensure the accuracy of your gene editing with CRISPR/Cas9 off-target screening services from CD Biosynsis.

But the wider impact of CRISPR technology in medicine involves not just its application to other genetic diseases, but also the ethical and social implications.

Other genetic disorders that CRISPR could treat: CRISPR technology isn't a strict sickle cell disease treatment but is also being applied to other genetic disorders such as beta-thalassemia, Duchenne muscular dystrophy, Huntington's disease, etc. All these trials show how much CRISPR could be used to target other diseases, and thus will be a powerful component of the next wave of precision medicine.

Moral and social controversy: CRISPR technology holds huge medical potential, but it has also caused a great deal of ethical and social debate. Particularly with germ cell editing, researchers are worried about unintended effects of gene editing over time. Equal access to gene editing could further breed social inequality.

The CRISPR gene editing toolkit has already proven efficacious in the treatment of sickle cell disease and other genetic diseases, and could change the way these diseases are treated in the future. But with the rise and proliferation of technology applications, equally important moral and social concerns also have to be fully considered and resolved. Access a variety of CRISPR Tools provided by CD Biosynsis to support your genome editing projects.

References

Zarghamian, Parinaz, Julia Klermund, and Toni Cathomen. "Clinical genome editing to treat sickle cell disease—a brief update." Frontiers in Medicine 9 (2023): 1065377.
Peretz, Sari, et al. "The protective effect of the spleen in sickle cell patients. A comparative study between patients with asplenia/hyposplenism and hypersplenism." Frontiers in Physiology 13 (2022): 796837.
Conran, Nicola, and Erich V. De Paula. "Thromboinflammatory mechanisms in sickle cell disease–challenging the hemostatic balance." Haematologica 105.10 (2020): 2380.
Demirci, Selami, Naoya Uchida, and John F. Tisdale. "Gene therapy for sickle cell disease: An update." Cytotherapy 20.7 (2018): 899-910.
Sonnaila, Shivakumar, and Shilpi Agrawal. "CRISPR-Cas9 Unleashed: Gene-Slicing Adventures in the Cancer Battlefield." Cancer Insight 2.2 (2024): 82-99.

Please note that all services are for research use only. Not intended for any clinical use.

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