28 February 2019

For the first time in the Western hemisphere

Therapy with CRISPR-intervention in stem cells is used to treat blood diseases

Lina Medvedeva, XX2 century

A private biotech company said it has combined CRISPR, a genome editing tool, and stem cell therapy for human treatment for the first time outside China.

Vertex Pharmaceuticals and CRISPR Therapeutics have announced that they have moved a step forward in the treatment of a patient with beta-thalassemia by using CRISPR/Cas9 therapy with modified hematopoietic stem cells. The developers called this type of therapy – CTX001.

Clinical trials of the new therapy have just begun, but so far everything is going well.

CTX001 is a new therapy currently being investigated, which CRISPR Therapeutics is developing for the treatment of hereditary diseases associated with a violation of the structure of hemoglobin (a protein that provides the ability of red blood cells to carry oxygen), in particular, sickle cell anemia and beta-thalassemia.

Human hemoglobin is a tetramer, that is, it consists of 4 protomers. In an adult, they are represented by the polypeptide chains α1, α2, β1 and β2. Such hemoglobin is called hemoglobin A.

Fetal hemoglobin (hemoglobin F) is a form of hemoglobin that is naturally present in newborns, but is subsequently replaced by an adult form (hemoglobin A). Hemoglobin F – as well as hemoglobin A is a tetramer, but consists of two α-chains and two γ-chains of globin. This variant of hemoglobin is also present in the blood of an adult, but normally it is less than 1% of the total amount of hemoglobin in the blood of an adult and is determined in 1-7% of the total number of red blood cells. However, in the fetus, this form of hemoglobin is dominant, the main one. Sometimes fetal hemoglobin persists in adults, providing protection to people with sickle cell anemia and beta-thalassemia.

Sickle cell anemia is associated with a mutation of the HBB gene that stimulates the production of abnormal hemoglobin S, in the molecule of which valine is located instead of glutamic acid in the sixth position of the β-chain. Under conditions of hypoxia, hemoglobin S polymerizes, as a result of which red blood cells acquire a crescent shape. The spectrum of symptoms of sickle cell anemia is extremely wide, from increased fatigue and swelling to ulcers on the legs, blockage of blood vessels in the liver and spleen and blindness, susceptibility to infections, developmental delays.

Beta-thalassemia occurs due to a defect in the beta-globin gene, which provides synthesis of polypeptide beta chains in the structure of hemoglobin. Shortly after birth, the body goes from producing gamma globin chains, which connect with alpha globin chains to produce fetal hemoglobin (hemoglobin F), to producing beta globin chains. The beta-globin chain connects to alpha-globin chains to produce adult hemoglobin (hemoglobin A). A defect in the beta-globin gene leads to a decrease in the number of beta-globin chains in people with beta-thalassemia. At the same time, there is an excess of free alpha-globin chains. Excessive alpha chains of globin do not form tetramers, but bind to the erythrocyte membrane and damage it. This leads to the destruction of red blood cells by the spleen and a decrease in the number of red blood cells in the body. The organisms of people with beta-thalassemia can continue to produce gamma globin chains in an attempt to increase the amount of hemoglobin F and compensate for hemoglobin A deficiency.

Symptoms of thalassemia also vary: from anemia, shortness of breath, fatigue to changes in the shape of the skull bones, liver enlargement, physical and mental underdevelopment.

Beta-thalassemia is usually treated with regular blood transfusions.

The creators of CTX001 have proposed a different approach. They obtained hematopoietic stem cells (blood cell precursors) from the patient's peripheral blood samples and, using CRISPR/Cas9, edited their genome so as to increase the level of fetal hemoglobin production in the patient's erythrocytes.

The blood cell elements created with CRISPR/Cas9 are capable of producing a lot of fetal hemoglobin, they carry more oxygen and can be returned to the patient's circulation.

It is important that not new, extraneous genes are introduced into the cells, but the patient's own genetic information is changed in order to activate his own gene for the production of his own fetal hemoglobin. There is also no editing of gametes (eggs or spermatozoa), which would lead to inherited changes affecting every cell of the body – the gene modification used in CTX001 affects only target cells.

"This is a huge progress in the study of CTX001, and we are pleased to announce that we have cured the first patient with beta-thalassemia in a clinical trial," says Dr. Samarth Kulkarni, head of CRISPR Therapeutics. – The treatment of the first patient in this study is an important scientific and medical milestone and the beginning of our research to justify the hopes for CRISPR/Cas9 as a new class of therapy that can transform the treatment of severe diseases."

In the near future, in mid-2019, the first phase of clinical trials of the use of CTX001 and for the treatment of sickle cell anemia will begin. Scientists have already selected the patient on whom the therapy will be tested.

"Beta-thalassemia and sickle cell anemia are serious, life–threatening diseases, and we are counting on treatment outside the body with CTX001 in order to create a single therapeutic effect," adds Dr. David Altshuler.

The press release of CRISPR Therapeutics and Vertex Announce Progress in Clinical Development Programs for the Investigational CRISPR/Cas9 Gene-Editing Therapy CTX001 is published on the website of CRISPR Therapeutics – VM.

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