Sickle cell disease is a genetic disorder that causes lifelong suffering—here’s what you need to know microbiologystudy

Right now, approximately 20 billion red blood cells are busy traveling through your blood vessels. They are delivering oxygen to all the different tissues in your body and removing carbon dioxide to be breathed out of your lungs.

Red blood cells are disks curved inwards on both sides, without a cell nucleus. They are full of hemoglobin, a protein responsible for gas exchanges. At the core of a hemoglobin molecule is an iron carrying component called heme, which can be loaded with oxygen.

The shape of the red blood cell is useful to flexibly navigate blood vessels of all sizes, deforming as needed. It also provides a large surface for gas exchange. Hemoglobin collects oxygen in the lungs, where there is plenty of it, and releases it across the body, where there is much less.

But not if you suffer from sickle cell disease, which affects nearly 8 million people worldwide, most in sub-Saharan Africa.

In the UK, approximately 17,500 people have sickle cell disease and 300 babies are born with the condition each year. It is a genetic disorder caused by inherited mutations in a person’s DNA that affect the properties of hemoglobin.

Hemoglobin is made up of four proteins organized around the iron-carrying heme group. These proteins are called globins, and each hemoglobin molecule has two alpha and two beta-globins.

Sickle cell disease changes adult beta-globin. Instead of two alpha and two healthy beta chains, sickle cell disease patients have two alpha and two mutant beta chains. The resulting hemoglobin is called HbS.

HbS has different characteristics to normal adult hemoglobin, causing severe symptoms. HbS is structurally unstable. Upon high temperatures, dehydration, acidity, such as happens during infections, it clumps inside the red blood cells. The clumps make red blood cells rigid and change their shape from flexible doughnuts into inflexible sickles—hence the name of the disease.

Rigid sickle cells cannot travel through narrow blood vessels, which clogs them, forming clots that stop blood circulation in different places. The clots change oxygen and acidity locally, causing more sickling.

Accumulation of clots causes some of the most severe symptoms of sickle cell disease, including strokes, kidney failure, blindness, prolonged and painful erections (called priapism) and loss of circulation in the lungs—the excruciating acute chest syndrome.

Repeated clotting scars and destroys the spleen, increasing the risk of recurrent infections, often by streptococcal bacteria which can cause severe pneumonia and sepsis.

Sickle red blood cells also break easily, a phenomenon called hemolysis. The body tries to produce more red blood cells, but cannot correct the underlying defect. Patients experience symptoms similar to other forms of anemia, including pallor, breathlessness upon exertion, fatigue. Hemolysis leads to inflammation and damages blood vessels, further aggravating sickling symptoms.

Lifelong suffering

Symptoms and complications of sickle cell disease start in the first year of life and progress in severity. The disease reduces the quality and duration of life of patients—in the UK, those with sickle cell disease have a life expectancy of 67.

Worldwide, life expectancy is below 50 and many children with sickle cell disease in sub-Saharan Africa die before the age of five. Sickle cell disease patients are dependent on transfusions of healthy red blood cells—over time this causes complications of its own.

Until recently, the only cure for sickle cell disease was stem cell transplantation—also known as bone marrow transplantation—from a healthy donor with a compatible immune system which will not be rejected by, or attack, the patient. Often, this is a sibling or a parent, but, in up to 75% of cases, a compatible relative cannot be found.

Stem cell transplantation replaces the cells in the blood factory of the patient, which produce HbS, with blood-making cells without the genetic defect, which produce normal adult hemoglobin. Transplanted blood stem cells maintain healthy hemoglobin production for life.

In the absence of transplantation, sickle cell disease patients receive regular transfusions, which deliver healthy red blood cells. But, unlike stem cells, red blood cells are short-lived.

Patients also receive a drug called hydroxycarbamide, which is used to treat cancer patients and can be toxic, but alleviates symptoms. Hydroxycarbamide acts by turning on a gene that leads to the production of fetal hemoglobin, which is not affected by the sickle cell disease mutation.

In 2024, two forms of gene therapy were approved for sickle cell disease treatment by the US Food and Drug Administration. Both involve collecting stem cells from the patient, modifying them genetically, and transplanting them back into the patient so the body makes blood with corrected cells for the rest of the patient’s life.

The first of the gene therapies, commercially called Casgevy, works by removing and inactivating a gene that is normally responsible for producing beta-globin. This replaces HbS in the red blood cells with the unaffected fetal hemoglobin.

The second gene therapy, called Lyfgenia (Lovotibeglogene autotemcel), works differently. It introduces an additional gene in the stem cells which makes it less likely for HbS to form aggregates and cause sickling, reducing the more severe symptoms of the disease.

The development and testing of gene and cell therapies for sickle cell disease is still an ongoing effort of many scientists and companies. That there are now two approved therapies for sickle cell disease highlights the importance of supporting investigation and development of breakthrough technologies based on detailed understanding of biological mechanisms of disease.

These investigations are key to treating patients with genetic diseases, which often do not have any other available treatments.

This article is republished from The Conversation under a Creative Commons license. Read the original article.