CRISPR-based Gene Therapy Shows Initial Promise Targeting Sickle Cell Disease & Thalassemia

CRISPR-based Gene Therapy Shows Initial Promise Targeting Sickle Cell Disease & Thalassemia

A painful inherited blood disorder affecting millions of people, especially Black people, occurs because of a deficiency of red blood cells to actually carry oxygen throughout the body. In a normal scenario these flexible, round red blood cells move about freely through the blood vessels. In the case of sickle cell anemia, these cells are shaped like sickles, sort of like crescent moons. A lifelong disease, the only known cure involves a blood and bone marrow or stem cell transplant, however  according to the National Heart, Lung and Blood Institute (NHLBI), part of the National Institutes of Health (NIH), there are treatments that help contribute to a reduction in symptoms while prolonging life. The Centers for Disease Control and Prevention (CDC) breakdown the different types of sickle cell disease. Beta thalassemia occurs in about 1 in 100,000 as well. The CDC estimates that least in America the disease afflicts approximately 100,000 people and occurs in about 1 out of every 365 Black or African American births. About 1 in 13 Black or African American babies  are born with a sickle cell trait. With the advent of  gene editing came newfound hope for sickle cell patients and their families and loved ones. Advanced new therapies known as regenerative therapy could revolutionize treatment for many gene-based diseases. Recently, partial results for a gene editing study involving CRISPR could possibly treat or even cure sickle cell disease and beta thalassemia. With partial results shared at an American Society of Hematology conference, as well as published by the New England Journal of Medicine, doctors reported on 10 patients who were treated several months ago and excitingly, no longer require regular blood transfusions and report next to no more pain. This treatment literally attacks the root cause of the disease, its genetic roots. Could a cure for genetic-based blood diseases be within reach with CTX001 (CRISPR Therapeutics & Vertex)?

The Patient: A Miraculous Story

Recently reported on by the Associated Press and Yahoo News, the first patient that enjoys the results of this amazing new gene editing approach, Victoria Gray, had long suffered from this disease, including severe bouts of pain that necessitated hospitalization. Ms. Gray, now 35, was treated with the CRISPR-based therapy a year ago, and reports she was able to get off of pain medication. She commented, “I had aching pains, sharp pains, burning pains, you name it. That’s all I’ve known my entire life. Anywhere Ms. Gray’s blood flowed, pain followed. However, since this treatment, a near miraculous change has occurred, one Ms. Gray says the prayers that others in the study benefit from. 

The Genetic Defect

As described in the recent AP piece, those with sickle cell for example actually have a genetic defect. As it turns out during the fetal period the fetus makes a particular kind of hemoglobin. Once the baby is born however, and the baby starts breathing a gene is triggered instructing cells to switch from fetal period to adult, thereby telling the system to produce adult hemoglobin. It is this adult hemoglobin that is actually defective in individuals with these blood diseases (sickle cell, thalassemia). Breakthrough new gene therapies, powered by CRISPR editing, can literally edit out the switching gene.

Enter the Cell Therapy Study

As reported in recent press, Dr. Haydar Frangoul of the Sarah Cannon Research Institute in Nashville reported on this novel approach “What we are doing is turning that switch back off and making the cells think they are back in utero, basically.” In this way, they actually revert to producing fetal hemoglobin again, reported Dr. Frangoul, a study leader. 

In this therapy, the treatment involves the actual removal of stem cells from the patient’s blood. Research investigators then employ CRISPR in the lab to actually “knock out the switching gene.” Other medications are apparently used to kill off other flawed blood-generating cells.  The team then infuses the lab-altered stem cells back into the patient. 

The results reported here involve the first of 10 patients, seven with beta thalassemia and three with sickle cell.  Both studies involve 45 patients, one in the U.S. and one in Europe. In one study (NCT03745287) is a single-arm, open-label, multi-site, single-dose Phase ½ study in subjects with severe sickle cell disease. IN this study the sponsors and investigators evaluate the safety and efficacy of autologous CRISPR-Cas9 Modified CD34+ Human Hematopoietic Stem and Progenitor Cells (hHSPCs) using CTX001.

The other study (NCT03745287) reported by these sponsors involves a multi-site, observational study to evaluate the long-term safety and efficacy of CTX001 in subjects who received CTX001 in Study CTX001-111 (NCT03655678) or Study CTX001-121 (NCT03745287). 

What is CTX001?

The investigational treatment involved in this study is known as CTX001. Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, this investigational product is under development to treat inherited disorders of hemoglobin such as sickle cell disease and beta-thalassemia. CTX001 is based on the use of gene-editing technology (again CRISPR) to alter a gene to actually increase the production of fetal hemoglobin in patients’ red blood cells. As discussed earlier, this form of hemoglobin occurs naturally in newborn babies. 

Investigators initially collect the patient’s hematopoietic stem cells, that is those stem cells originating in bone marrow that actually are the genesis of all red and white blood cells. Once collected, the study investigators then modify these cells in a laboratory, essentially reengineering these cells so that they can generate high levels of fetal hemoglobin. 

Regulatory Status of CTX001

To accelerate the development and regulatory review in consideration of those ill with these genetic-based diseases, The U.S. Food and Drug Administration (FDA) originally granted the important classification of fast track designation back in January 2019.  And by May 2020 the FDA designated CTX001 a regenerative medicine advanced therapy (RMAT) for treating severe sickle cell diseases and transfusion-dependent thalassemia. As reported by Sickle Cell Disease News, this RMAT designation helps expedite new therapies that can address life-threatening medical conditions, or if the novel therapy can evidence material benefit over existing therapies.

Study Sponsor

This study was sponsored by CRISPR Therapeutics based in Zug, Switzerland and Vertex Pharmaceuticals based in the Boston area.

Key Centers of Excellence for Regenerative Therapies

These studies are occurring at prominent academic medical centers in both the United States and Europe. Serving as trial site organizations for sickle cell disease and thalassemia, these are centers of excellence for advanced treatment of these genetic disorders. They include:

  • Lucile Packard Children’s Hospital of Stanford University (Palo Alto)
  • University of Illinois at Chicago Hospitals and Health Systems (Chicago)
  • Columbia University Medical Center (New York City)
  • Children’s Hospital of Philadelphia (Philadelphia)
  • St. Jude Children’s Research Hospital (Nashville)
  • The Children’s Hospital at TriStar Centennial Medical Center/ Sarah Cannon Center for Blood Cancers
  • Methodist Children’s Hospital/Texas Transplant Institute (San Antonio)
  • Hopital Universitaire des Enfants Reine Fabiola (HUDERF) (Brussels, Belgium)
  • The Hospital for Sick Children (Toronto)
  • Regensburg University Hospital, Clinic and Polyclinic for Paediatric and Adolescent Medicine, Paediatric Haemotology, Oncology and Stem Cell Transplantation (Regensburg, Germany)
  • Dipartimento di Onco-Ematologia e Terapia Cellulare e Genica Ospedale Pediatrico Bambino Gesu – IRCCS (Rome, Italy)
  • Imperial College Healthcare NHS Trust, Hammersmith Hospital (London)

Call to Action: Does a loved one in the family have sickle cell disease or thalassemia? Look into these studies and trial site centers. Feel free to contact TrialSite for assistance.