Gene therapy for hemophilia and sickle cell disease

New treatments for hemophilia and sickle cell disease (SCD) that are based on gene therapy have been approved by the United States Food and Drug Administration (FDA)^1-2. They are inherited diseases that are caused by missing or defective genes that code for proteins that are essential for healthy red blood cells. These cells must contain hemoglobin to carry oxygen throughout the body and form blood clots when bleeding occurs. Hemophilia causes blood not to clot. This can lead to uncontrolled bleeding and death. SCD occurs when a harmful form of hemoglobin is made. The red blood cells become hard and sticky and look like the C-shaped farm tool called a sickle. In the past, it has been difficult to treat or control hemophilia and SCD.

There are three types of hemophilia³. The most common is hemophilia A, also called factor VIII (8) deficiency or classic hemophilia. It is a genetic disorder caused by a missing or defective clotting factor called VIII (FVIII), a clotting protein. Although it is passed down from parents to children, about 1/3 of cases found have no previous family history. Hemophilia B and C are caused by a deficiency of blood clotting factors IX (9) and XI (11), respectively.

Sickle cell disease (SCD) is a group of inherited red blood cell disorders. In SCD, the red blood cells become hard and sticky and look like a C-shaped farm tool called a “sickle.” Still, people with SCD can live full lives and enjoy most of the activities that other people do. In patients with SCD and beta-thalassemia, the adult hemoglobin is defective. SCD is a genetic condition that is present at birth. It is inherited when a child receives two genes—one from each parent—that code for abnormal hemoglobin.

That is, blood clots are formed in a process that requires several proteins that are called factors. They work together to stop bleeding. Factor I (1) is also called fibrinogen. It is converted into an adhesive or sticky protein called fibrin. Fibrin binds to red blood cells and platelets to make a fibrin clot. There are three biochemical pathways involved in forming blood clots. There are intrinsic, extrinsic, and common" pathways. These pathways inside the blood turn on (activate) each other to stop bleeding.

Fibrin is in the common pathway. There is also factor II (2) that is also called prothrombin. When it is activated, it changes into thrombin, which later helps fibrinogen become fibrin. Next, there is tissue factor 3(III). It functions as a switch that initiates blood clotting when bleeding starts. It's located outside the blood in body tissues and initiates clotting when there is damage. It initiates the extrinsic pathway. Then, factor 5 (V) joins with factor 10 (X) in the common pathway to change prothrombin into thrombin. Also, factor 7 (VII) joins binds to a tissue factor to start the clotting process in the extrinsic pathway. Then there is factor 8 (VIII). It's a helper. It binds to factor IX (9). Without factor 8 (VIII), factor 9 (IX) can't do its job well. When factor VIII (8) and factor IX (9) bond together, they can activate factor 10 (X). Factor VIII (8) is in the intrinsic pathway. Factor 9 (IX) works with factor 8 (VIII) to activate factor X (10). Without it, clotting can't occur. Factor 9 (IX) is in the intrinsic pathway. Factor X (10) is the activating factor that starts the common pathway. Once activated, factor X (10) helps change factor 2(II) (prothrombin) into thrombin. Factor 11(XI) starts the intrinsic pathway. When it's activated, it helps activate factor 9 (IX). Once the fibrin clot is made, factor 13 (XIII) ensures that it's strong and doesn't fall apart. It is in the common pathway. Finally, the von Willebrand factor (vWF) secures factor 8 (VIII) as it moves toward factor 9 (IX).

Once the common pathway starts, either from the extrinsic pathway or intrinsic pathway, thrombin changes fibrinogen into fibrin. This helps make a strong clot. Then, factor 13 (XIII) is activated and helps make a net-like structure to keep the blood clot in its place.

According to the United States Centers for Disease Control and Prevention (CDC), hemophilia occurs in approximately 1 in 5,617 live male births. There are between 30,000 – 33,000 males with hemophilia in the United States. More than half of people diagnosed with hemophilia A have the severe form. Hemophilia A is four times as common as hemophilia B. Hemophilia affects all ethnic groups. It is a sex-linked disorder. The X and Y sex chromosomes help determine hemophilia inheritance patterns. The gene for hemophilia is carried on the X chromosome. It is inherited in an X-linked recessive manner. Females inherit two X chromosomes, one from their mother and one from their father (XX). Males inherit an X chromosome from their mother and a Y chromosome from their father (XY). That means if a son inherits an X chromosome carrying hemophilia from his mother, he will have hemophilia. It also means that fathers cannot pass hemophilia on to their sons. Still, daughters have two X chromosomes. Even if they inherit the hemophilia gene from their mother, most likely they will inherit a healthy X chromosome from their father and not have hemophilia. A daughter who inherits an X chromosome that contains the gene for hemophilia is called a carrier. She can pass the gene on to her children, even though she does not have the disease itself. However, many women who carry the hemophilia gene have a deficiency of clotting factors. This can result in heavy menstrual bleeding, easy bruising, and bleeding in the joints. Some women who have the hemophilia gene have factor expression low enough to be diagnosed with hemophilia.

The biotechnology company CSL Behring produces the gene therapy treatment for hemophilia B called Hemgenix® (etranacogene dezaparvovec) ⁴. It uses an adeno-associated virus (AAV) vector to deliver the proper gene. Adenoviruses have been used for decades to produce a variety of safe and effective vaccines, including some for Covid-19 ⁵. In a phase III clinical trial called HOPE-B, Hemgenix® was given to patients who had severe or moderately severe hemophilia B with or without pre-existing AAV5 neutralizing antibodies ⁶. The mean annualized bleeding rate for all bleeds was reduced by 64% during months 7-36 of the study. Moreover, 94% (51 out of 54) of patients were able to forgo continuous prophylactic therapy. There were no serious adverse events related to treatment. The therapy was generally well-tolerated, with most (76%) treatment-emergent adverse events (TEAEs) considered mild. Further, 95% of TEAEs occurred before six months post-treatment. These results indicate that a one-time treatment with Hemgenix® can produce elevated and sustained concentrations of factor IX and reduce the rate of annual bleeds for years in people living with hemophilia B.

In the meantime, the FDA approved two cell-based gene therapies for SCD ⁷. SCD is a group of inherited blood disorders associated with an abnormality in the hemoglobin protein, which normally helps carry oxygen throughout the body via red blood cells. This causes red blood cells, normally disc-shaped and flexible enough to travel smoothly in the body, to become rigid and misshapen to resemble a “C” or sickle. The resulting symptoms include anemia, swelling of the extremities (hand and feet), frequent infections, vision problems, stroke, and very severe pain in the chest, abdomen, and joints. Another major impact on patients is severe pain and organ damage called vaso-occlusive events or vaso-occlusive crises – an accumulation of these events can result in physical disabilities and even death. The majority of SCD cases in the USA are found in people who are of African ancestry or identify themselves as black.

On December 8, 2023, the FDA approved Casgevy™ (Vertex Pharmaceuticals Inc.) and Lyfgenia™ (Bluebird Bio Inc.). They are both innovative cell-based gene therapies. They are produced using the patients’ own blood stem cells, which are removed and genetically modified, then transplanted back as a one-time, single-dose infusion. CasgevyTM is indicated for the treatment of SCD patients 12 years of age and older with recurrent VOCs. It is the first FDA-approved therapy to develop the genome editing technology known as CRISPR/Cas9. This technology has been described previously in this journal ^8-9.

Casgevy™ is the world's first approved CRISPR-based therapy. It is also known as Exa-cel. It received its first regulatory approval on Nov. 16, 2023 from the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) to treat two debilitating blood disorders: sickle cell disease and transfusion-dependent beta-thalassemia. These are lifelong genetic disorders caused by mutations in the genes that code for hemoglobin. Beta-thalassemia affects around 1 in 100,000 people worldwide. It disproportionately affects people of Mediterranean, Asian, African, and Middle Eastern descent. Patients with beta-thalassemia don't produce enough hemoglobin, which can lead to severe anemia, whereas sickle-cell anemia stems from a lack of healthy red blood cells.

CasgevyTM targets the gene BCL11A which codes for a protein that would normally regulate the switch from the fetal version of hemoglobin to the adult version shortly after birth. However, in patients with SCD and beta-thalassemia, the adult hemoglobin is defective. CasgevyTM disables BCL11A. This allows the body to keep making fetal hemoglobin. Stem cells that make other blood cells are taken from a patient's bone marrow. The BCL11A gene is edited in the lab. The newly-modified cells with functioning hemoglobin are then infused back into the patient's body. Before the infusion, the patient must take a chemotherapy drug called busulfan to eliminate the unedited cells still in their bone marrow. This process of adjusting to the new, edited cells is lengthy. It takes at least a month in a hospital facility for the treated cells to take up residence in the bone marrow and to start making red blood cells that contain the stable form of fetal hemoglobin. In two clinical trials, CasgevyTM restored hemoglobin production in most patients with SCD and beta-thalassemia and alleviated their symptoms. Twenty-eight out of 29 patients with SCD didn't experience any severe pain for at least a year after being treated. Similarly, 39 out of 42 patients with beta-thalassemia didn't need red blood cell transfusions during the same post-treatment period. The remaining three patients were more than 70% less likely to need a transfusion. Both of these trials are ongoing, and Casgevy's long-term safety continues to be monitored by regulatory bodies, such as the MHRA and the FDA, and by the therapy's manufacturers, Vertex Pharmaceuticals and CRISPR Therapeutics. Moreover, the treatment is currently being reviewed by the European Union's European Medicines Agency and the Saudi Food and Drug Authority.

Lyfgenia is approved for the treatment of patients 12 years of age and older with SCD and a history of vaso-occlusive events. It uses a lentiviral vector to deliver the modified genetic material.

So, after decades of work and many disappointing results in treating other diseases, gene therapy is now becoming safe and effective. Scientists, doctors, and corporations are working with non-profit foundations such as the National Bleeding Disorders Foundation (NBDF) to develop new therapies to treat genetic diseases ¹⁰.