Foetal Haemoglobin to avert sickle cell disease: so near yet, so far away.

Foetal Haemoglobin to avert sickle cell disease: so near yet, so far away.

Haemoglobin is the protein responsible for carrying and delivering oxygen to the tissues from the lungs. We find it in the red blood cells. Several types of haemoglobin exist: however, foetal haemoglobin (HbF), adult haemoglobin (HbA), sickle haemoglobin (HbS), and haemoglobin C (HbC) are pertinent to today’s discussion.

Foetal Haemoglobin to avert sickle cell disease: so near yet, so far away.
Haemoglobin, molecular model. Haemoglobin is a metalloprotein that transports oxygen around the body in red blood cells. Each molecule consists of iron-containing haem groups (sticks) and globin proteins (amino acid chains, coils). Each globin protein is wrapped around a haem group, protecting it from being oxidised and destroyed by the oxygen it is intended to transport. The iron within each haem group reversibly bonds to oxygen and carbon dioxide in the blood.

Since the first report in 1910, sickle cell disease has evolved to become the most prevalent genetic disease globally. It disproportionately affects Africans regardless of their geographic location. A few Hispanics, Middle Eastern, southern Europeans, and Indians become culprits.

For decades, sickle cell disease continues to afflict pain, suffering, and loss among the population – curtailing the already short lifespan of Africans. Despite this observation, research into finding possible cures had stalled due to a chronic lack of funding globally. A lot has changed since the discovery of hydroxyurea in the 1960s. Previously, people only relied on blood transfusions to ameliorate sickle cell disease complications. Recently, the FDA approved voxelotor as another novel drug besides hydroxyurea.

Foetal haemoglobin represents an unchartered arena that awaits us to navigate as its induction suppresses sickle haemoglobin production – the pinnacle of sickle cell complications.

Scientists have continuously channelled their insights towards a particular haemoglobin molecule that all children are born with, which wanes as they grow after birth. We call it foetal haemoglobin.

When children are born, their red blood cells contain foetal haemoglobin. As they grow, adult haemoglobin replaces the foetal type. Sickle haemoglobin is the abnormal protein that results when a mutation occurs in one of the globin chains of adult haemoglobin (the beta-globin chain). In children with the defective gene, as foetal haemoglobin wanes, sickle haemoglobin replaces it instead of adult haemoglobin. The manifestation of the effects from this inborn error depends on the percentage of HbS a person has. Children who carry only one defective gene (heterozygotes) do not show any disease symptoms. We call them carriers. Those that inherit both aberrant genes (homozygotes) show a full-blown disease – sickle cell anaemia. However, among children with sickle cell anaemia, the disease manifests at different ages – from as early as three months to as late as ten years. The difference among the different ages may be due to the rate of the waning of foetal haemoglobin.

Foetal Haemoglobin to avert sickle cell disease: so near yet, so far away.
A ball and stick + ribbon model of Human Hemoglobin, the protein in red blood cells which transports oxygen around the body.

Unlike HbS, HbF does not sickle. If a child has the defective gene; but their HbF levels remain high in circulation, they cannot show signs and symptoms of sickle cell anaemia. With this apparent knowledge, one may wonder why it has taken so long to find treatment modalities that focus on inducing/ maintaining HbF production while downregulating HbS generation. One of the main obstacles to finding a cure for sickle cell disease has been funding. For years, research into sickle cell disease has been slow. Recent advances in gene therapy have enabled scientists to identify the gene (BLC11a) responsible for repressing HbF production. During the quest, scientists have employed CRISPR-Cas9 to disrupt the gene. Others have used a lentiviral vector to downregulate it. Downregulation of the gene induces HbF production as well as suppresses HbS synthesis. The result is an abundance of HbF that does not sickle, a feat that renders a sickle cell crisis-free life among children with sickle cell disease.

However, all these trials are still limited in what they can achieve since the enrolment is still low. The technology is still in its infancy. A dire need for more funding into sickle cell disease research projects is apparent: to scale up such modalities and expedite their FDA approval for use by the general population. It is also prudent that when such treatment modalities become available, they should be affordable. The fact remains that sickle cell disease afflicts more impoverished people than the rich. For the wealthy, a bone marrow transplant is a credibly viable option. The poor only have hydroxyurea to avert the symptoms. Less than 1% of the affected population can afford the novel voxelotor.

Foetal haemoglobin has been with us since the genesis of life on earth. It is within our reach to further understand its uses beyond carrying oxygen to the foetus in utero. Yet, the ability to target it as a treatment modality in a disease that has afflicted pain, suffering, and loss among Africans seems so far away at the moment. Complete remission of sickle cell disease lies in the genes that cause it. We need more funding to make this novel modality a day-to-day treatment plan for all.

Foetal haemoglobin represents an unchartered arena that awaits us to navigate as its induction suppresses sickle haemoglobin production – the pinnacle of sickle cell complications.


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