Sickle cell illustration (National Heart, Lung, and Blood Institute)
19 Nov. 2019. Early results from a clinical trial testing gene editing treatments for inherited blood disorders show the treatments helped patients improve their conditions. Findings from the first two patients in the clinical trial, including serious adverse effects, are reported today by developers of the therapies, Vertex Pharmaceuticals in Boston and CRISPR Therapeutics in Cambridge, Massachusetts.
The experimental therapy code-named CTX001 is designed to treat patients with genetic defects causing 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.
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.
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 early- and mid-stage clinical trial is recruiting 45 adult participants at sites in the U.S., Canada, and Europe with severe sickle cell disease and beta thalassemia. The study team is looking primarily for signs of adverse effects from the treatments, but also evidence of engraftment, where blood-forming stem cells begin to make new red and white blood cells and platelets. Researchers will track participants for two years.
Vertex and CRISPR Therapeutics say several participants are now enrolled in the trial — the exact number was not disclosed — and reported on results from the first two patients receiving CTX001. One of the participants has sickle cell disease and the other has beta thalassemia, with each patient receiving one CTX001 infusion.
The patient with sickle cell disease experienced an average of seven painful episodes in the two years before joining the trial. The researchers say this individual experienced engraftment of neutrophils, white blood cells in the immune system, and platelets after 30 days. In the four months following the infusion, the patient experienced no painful sickle cell episodes.
The participant with beta thalassemia required an average of 16.5 transfusions in the two years before the trial. The study team reports the patient achieved neutrophil engraftment in 33 days and platelet engraftment in 37 days after receiving CTX001. In the nine months following the infusion, the participant became transfusion independent, requiring no further transfusions.
However both participants reported serious adverse events during the trial. The sickle cell patient experienced sepsis, gallstones, and abdominal pain, while the beta thalassemia participant experienced pneumonia and veno-occlusive liver disease, where small blood vessels leading to and inside the liver are blocked. The study team says these adverse effects were not related to CTX001 treatments and resolved in each case.
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