Introducing British-198 Mutation May Lead to Cure for Hemoglobinopathies

Possible cure to blood disorders through gene therapy; addition of a favorable gene mutation raises fetal hemoglobin levels.

Highlights:

Hemoglobinopathies including sickle cell anemia and thalassemia are caused due to genetic mutations resulting in abnormal production of red blood cells.
Increasing fetal hemoglobin (HbF) levels is a possible cure to diseases like sickle cell anemia.
Gene therapy was used to introduce a naturally favorable mutation in blood forming tissue that in turn increases HbF levels.

Gene therapy was used to turn on the fetal hemoglobin (HbF) gene in HUDEP-2 cells (adult human red blood cell precursor), which is a model of the cells that form red blood cells in humans. HbF gene is usually turned off after birth resulting in low fetal hemoglobin levels. However, some individuals have increased HbF levels even in adulthood, a condition called Persistence of Fetal Hemoglobin (HPFH). Further, increased HbF levels in individuals suffering from genetic blood disorders result in milder symptoms. Introducing the HPFH responsible mutation in sickle cell anemic and thalassemia patients may ultimately lead to a cure for these hemoglobinopathies.

Hemoglobinopathies

Hemoglobinopathies, including sickle cell anemia (SCA) and thalassemia are diseases that have damaged or abnormal hemoglobin production. Hemoglobin is the oxygen-carrying molecule in blood cells that transport oxygen throughout the body. Thereby, hemoglobinopathies are inherited blood disorders that result in abnormal or quantitative or qualitative hemoglobin production.

Sickle Cell Anemia:

SCA is an inherited red blood cell disorder where the cells acquire a sickle shape instead of the normal spherical shape. This is caused due to a single mutation in the hemoglobin beta gene. The sickle cells have reduced oxygen carrying capacity and get clogged in blood vessels leading to anemia and severe pain. Since it is inherited in an autosomal recessive manner, a child may be affected with sickle cell anemia if both parents are affected or if both parents are carriers for the mutation.

Thalassemia - Symptoms, Diagnosis, Treatment, Future Therapies
Thalassemia is an inherited blood disorder passed on through parental genes causing the body to produce abnormal hemoglobin.

‘Addition of the naturally occurring beneficial British-198 mutation in patients with genetic blood disorders elevates their fetal hemoglobin level and thereby reduces symptoms.’

Thalassemia:

Thalassemia is also an inherited blood disorder that affects the production of hemoglobin. In this disease the body is unable to produce hemoglobin or is able to do so in an insufficient amount. Depending on which gene is mutated thalassemia maybe alpha or beta thalassemia. Thalassemia maybe caused due to various mutations in hemoglobin production genes.

Current treatments for hemoglobinopathies

Medications
Blood transfusion
Bone marrow transplants

However, all these have potential ill effects. While medications have a wide range of side effects, blood transfusion has possibilities of infection and rejection. Bone marrow transplants, on the other hand, have an additional burden of finding a matching donor.

Gene Therapy Saves Life of Teenager with Sickle Cell Anemia
Teenager with sickle cell disease achieved complete remission after an experimental gene therapy.

Gene therapy

Gene therapy is a procedure that involves treating genetic diseases at the root cause, the genes. It uses one of the following to do so:

Replacing a faulty disease causing gene with a healthy one
Inactivating or knocking out a faulty gene
Introducing new genes to help fight disease.

In this study conducted at the University of New South Wales, researchers introduced a mutation using CRISPR into model human blood cells to increase fetal hemoglobin (HbF) levels. According to previous studies, it was identified that some patients with blood disorders carried an inborn natural mutation that resulted in 20% more HbF levels which resulted in milder symptoms of the disease. This extra fetal hemoglobin has strong affinity for oxygen and hence performs the function of the defective adult hemoglobin. This factor was put into practice in this study published in the journal Blood.

Out of the many variants of the naturally occurring mutation, British-198 was used for the study. It is called so because it was first identified in a British family and the mutation occurs in the 198th nucleotide position of the gene. The British-198 was introduced into HUDEP-2 cells. The cells that were edited showed substantially elevated levels of HbF. This gene editing therapy maybe used as a therapy for blood disorders if the British-198 mutation is introduced in the blood forming stem cells from the patient.

Concluding with the words of the senior author, Professor Merlin Crossley, “Because this mutation already exists in nature and is benign, this 'organic gene therapy' approach should be effective and safe to use to treat, and possibly cure, serious blood disorders. However, more research is still needed before it can be tested in people.”

Research Center For Blood Disorders To Be Set Up By ICMR In Maharashtra
The purpose of the center set up by Indian Council of Medical Research is to carry out research on hemoglobinopathies, which are a kind of genetic defect.

References:

Beeke Wienert, Gabriella E. Martyn, Ryo Kurita, Yukio Nakamura, Kate G.R. Quinlan, Merlin Crossley. KLF1 drives the expression of fetal hemoglobin in British HPFH. Blood, 2017; blood-2017-02-767400 DOI: 10.1182/blood-2017-02-767400
What is gene therapy? - (https://ghr.nlm.nih.gov/primer/therapy/genetherapy)

Source-Medindia