Trials Underway Testing Crispr for Blood Disorders

27 February 2019. Clinical trials testing the genome editing technique Crispr for sickle cell disease and beta thalassemia, two inherited blood disorders, enrolled and infused their first patients. The studies are conducted by Crispr Therapeutics and Vertex Pharmaceuticals, in Cambridge and Boston, Massachusetts respectively, developers of their joint product code-named CTX001 based on Crispr, for treating these diseases.

Crispr, short for clustered, regularly interspaced short palindromic repeats, makes it possible to edit genomes of organisms harnessing bacterial defense mechanisms that use RNA to identify and monitor precise locations in DNA. With CTX001, the actual editing is done by Crispr-associated protein 9, or Cas9, enzyme that programs RNA to silence genes and provide immunity against invading genetic material. Cas9 also harnesses RNA to cut DNA at precise points in genomes, making it possible to delete, insert, or correct defects in human genomes.

Genomic defects in these patients result in sickle cell disease and beta thalassemia. Sickle cell disease is a genetic blood disorder affecting hemoglobin, a protein in blood that delivers oxygen to cells in the body. People with sickle cell disease have hemoglobin molecules that cause blood cells to form into an atypical crescent or sickle shape. That abnormal shape causes the blood cells to break down, lose flexibility, and accumulate in tiny capillaries, leading to anemia and periodic painful episodes. People with beta thalassemia have lower production of hemoglobin in their blood.

CTX001 is designed to edit the patient’s own blood-forming stem cells to correct the errant genes responsible for these inherited diseases. Stem cells are edited with Crispr to produce high levels of healthy fetal hemoglobin, a type of the protein in the blood of newborns, later replaced by adult hemoglobin. The higher levels of fetal hemoglobin from CTX001 are intended to reduce the painful sickle-cell episodes and lower the number of transfusions needed by beta thalassemia patients.

The companies say the clinical trial for beta thalassemia infused its first patient, making it the first company-sponsored use of Crispr-Cas9 as a therapy in a clinical study. The early- and mid-stage trial is recruiting 45 participants with transfusion-dependent beta thalassemia in Canada, Germany, and the U.K, who receive one dose of their edited stem cells. The study team is looking for signs of adverse effects from the treatments, as well as changes in the need for blood transfusions over 24 months. Researchers are also checking on any genetic modifications in white blood cells and bone marrow cells, as well as changes in fetal hemoglobin concentrations over this period.

The sickle cell disease clinical trial enrolled its first patient at the study’s only site in Nashville, Tennessee. This early- and mid-stage study is also recruiting 45 participants with severe sickle cell disease, and as with the beta thalassemia study, they receive a single dose of their Crispr-edited stem cells. The study team for this trial is looking primarily for reports of adverse effects and fetal hemoglobin concentrations over 24 months, but also the number of severe painful episodes from sickle cell disease over this period, and genetic alterations in white blood cells and bone marrow cells.

The trials got off to a rocky start when, as reported by Science & Enterprise in May 2018, the Food and Drug Administration asked the companies to delay the start of the sickle cell disease trial until questions from the agency were resolved. The beta thalassemia trial in Europe reportedly was not affected by FDA’s delay.

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