The CRISPR solution to a sickly disease

A clinical trial that’s attempting to discover a cure for sickle cell disease has found a new gene therapy that’s safe and successful, writes Dr Praveen Kumar Kaudlay

What is common to former footballer Zinedine Zidane, former tennis player Pete Sampras and Indian actors Amitabh Bachchan and Jackie Shroff? All these famous personalities have a blood condition called thalassemia. Blood is the most important organ of the body. It has a red pigment called haemoglobin that helps in carrying oxygen to the different organs. This function facilitated by the haemoglobin has two pairs of non-identical chains wound around. As we grow from the foetal stage, the haemoglobin type also changes from a foetal type of haemoglobin called HbF to an adult type of haemoglobin called HbA and HbA2.

The oxygenation process is impaired when this haemoglobin is not at adequate levels. It results in a person feeling tired, weak, or short of breath. There are disorders passed down in the families that result in a defective haemoglobin structure or reduced haemoglobin production or none in severe cases.

The genetics of sickle cells

As the name suggests, sickle cell disease is one such condition due to defective haemoglobin where the structure of red cells shape up like a sickle. The normal red blood cells have a biconcave disc structure enabling them to flow easily within the blood vessels. In sickle cell disease, the sickled red cells can’t navigate easily through the blood vessels as their outer covering has become rigid. There is a spectrum within this condition. Those individuals who have a single chain defect are called carriers who have milder symptoms compared to those who have inherited the disease from both parents, which is called Sickle Cell Anaemia (SCA).

Similarly, carriers of thalassemia have milder anaemia compared to those who have a full-blown condition called Thalassemia Major. India has a significant burden with thalassemia and half of the world’s burden of sickle cell disease. There is a hypothesis that these conditions evolved to be protective against malarial infections. Sickle cell anaemia is more common among the tribal populations of the country in the states of Madhya Pradesh, Chhattisgarh, Odisha, Jharkhand, and Gujarat. Thalassemia is present across India among different communities. Estimates are that India has about 1,00,000 patients with Beta Thalassemia and 1,50,000 cases of sickle cell disease. The severe forms of Thalassemia (Major) require regular blood transfusions as the body does not produce enough haemoglobin. These patients develop growth delays, skeletal abnormalities, enlargement of the spleen and develop heart problems. Accessibility to safe blood is a big problem in India as blood availability depends on a privately collected pool. Repeated blood transfusions in these patients result in iron getting deposited in internal organs as blood contains iron and causes damage to organs. There are drugs used to remove excess iron called chelators, but again, the cost factor comes to play.

Crisis episodes

Sickle cell disorders cause episodes of pain as the blood cells get trapped inside the narrow blood vessels. Indian sickle cell patients tend to have lesser painful episodes something observed among the Arab types as opposed to Afro-Caribbean ones who get a lot more painful episodes. Fresh blood from healthy blood donors is administered to reduce sickle blood cells. In the event of severe complications, blood is cleaned through a machine called exchange transfusion. A drug called Hydroxycarbamide is used in these patients to reduce the incidence of crisis episodes.

For a long time, there has been an unmet need to have better treatment options available to both thalassemia and sickle cell anaemia patients.

Newer research is focusing on ways to reduce these sickle-shaped blood cells from getting attached to the inside of the blood vessels through a drug called Crizanlizumab. Repeated attendance to the hospital either for regular blood transfusions as in the case of thalassemia or hospitalisations for a painful crisis as in sickle cell anaemia reduces the quality of life.

CMC Vellore is one of the largest centres that perform bone marrow transplantation for thalassemia patients in India, more than 800 transplants have been done in this centre to date. “Considering the thalassemia load in our country, less than two percent of the patients needing a transplant are getting the transplant done, the cost of the procedure and lack of a suitably matched sibling as a bone marrow donor remain a major challenge,” observes Dr Vikram Mathews, Haematologist and Director of CMC Vellore.

Gene therapy against
invading viruses

The Mediterranean countries that have a significant number of cases of thalassemia can screen out minor patients and through counselling, prevent marriage between minors. Dr Vikram stresses good education and a robust antenatal diagnosis in India as a way forward to prevent major diseases from being born. The latest on the horizon is a novel gene therapy called CRISPR/Cas 9 or Clustered Regularly Interspaced Short Palindromic Repeats. Emmanuelle Charpentier and Jennifer Doudna were both awarded the 2020 Nobel Prize in Chemistry for their work on CRISPR-Cas 9 a method to edit DNA that forms the backbone of living beings. The concept for this innovation is derived from the knowledge existing since the 1980s of how bacteria have stretches in their DNA called CRISPR that are used as weapons against invading viruses. Using the CRISPR gene editing technology, Stem cells (mother cells) of thalassemia and sickle patients are edited in such a way that the production of haemoglobin present in the foetus called HbF is increased as it has more capacity to carry oxygen. This in turn reduces the frequent blood transfusion needs in thalassemia patients and reduces the painful episodes in sickle cell patients. It will take time before this technology is further refined and made widely applicable and of course, the cost of the treatment would be prohibitively expensive.

(The author is a consultant haemato-oncologist with a special interest in stem cell transplantation at Royal Wolverhampton NHS Trust, UK. He can be reached at [e-mail])