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CRISPR CTX001 Clinical Trial:

Promising Results in Sickle Cell
Patients
CRISPR CTX001 Clinical Trial:
Promising Results in Sickle
Cell Patients
POSTED: DECEMBER 09, 2020

Sickle cell anemia and beta-thalassemia are serious genetic blood disorders, caused
by mutations in the gene that produces beta-globin, a component of hemoglobin.
People afflicted by either disease suffer from anemia, pain attacks, fatigue, and risk
of organ damage, all of which impact their quality of life. Frequent blood
transfusions to alleviate symptoms or bone marrow transplants as a long term
solution have been the only treatment options so far.

The recent genome engineering revolution has sparked interest among researchers
to treat these diseases using gene therapy. As hematopoetic stem cells are
relatively accessible for ex vivo editing, sickle cell anemia and beta-thalassemia
have become prime candidates for gene therapy studies. In our other
comprehensive guide, we have covered how CRISPR is being used in sickle cell
anemia research and treatment.

In this blog post, we specifically report the triumph of CTX001 therapy, a

CRISPR-based investigational drug that is being tested in clinical trials for treating
sickle cell disease and beta thalassemia. Recent reports indicate that CTX001,
developed by Vertex Pharmaceuticals and CRISPR Therapeutics, has been effective
in restoring hemoglobin levels and alleviating symptoms in patients for more than a
year now. Partial data were presented at the American Society of Hematology 2020

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conference last week and details of data from two patients were published in the
New England Journal of Medicine.

CTX001 Mode of Action: CRISPR Editing to Boost

Fetal Hemoglobin Levels

Sickle cell anemia is caused by a specific single nucleotide mutation in the

beta-globin gene, which results in crescent or sickle-shaped red blood cells. Beta
thalassemia is an outcome of different types of mutations in the same gene,
resulting in reduced levels of hemoglobin. There are several approaches being
tested to treat SCD and beta-thalassemia that aim to fix the mutations associated
with the diseases. The CTX001 therapy takes an alternative approach.

Fetal hemoglobin is a form of hemoglobin in fetuses that has the same function as
regular hemoglobin but does not require the beta-globin subunit (uses
gamma-globin instead). After birth, production of this form of hemoglobin is
suppressed and is substituted by the regular form of adult hemoglobin, one that
requires functional beta-globin.

CTX001 is an autologous therapy, wherein a patient’s own cells are edited and used
for the treatment. Hematopoetic stem cells were surgically extracted from the bone
marrow of trial participants. Then, CRISPR was used to edit the BCL11A gene,
repressor of fetal hemoglobin (Hbf) expression, in their cells. Restoring fetal
hemoglobin levels could circumvent the harmful effects of deleterious mutations in
both diseases and afford a normal life for patients. These edited stem cells were

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introduced back into the patients and their progress was monitored through
regular check-ups every few months.

CTX001 Clinical Trial: Patient Data Shows Promising Results

The promising progress of Victoria Gray, the first trial participant for sickle cell
disease treatment, a year after her treatment this July had already kindled hopes of
CTX001 as an effective therapy. As per the data presented at the ASH 2020
conference, a total of 10 patients—three with SCD and seven with
beta-thalassemia—have shown great progress. They show significant fetal
hemoglobin levels in their blood, have relief from pain bouts, and have gone
several months without transfusion.

In a detailed report published in NEJM, data from two patients, one for each
disease, treated with CTX001, were reported. The highlights were as follows:

SYNTHEGO’S THE BENCH BLOG |CRISPR CTX001 Clinical Trial: Promising Results in Sickle Cell
Patients

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 ● High levels of allelic editing efficiency was maintained in bone marrow cells
and blood cells
● Increasing levels of hemoglobin were observed in both patients from 3-15
months
● After 12 months, blood reports already showed >98% of erythroyte cells
prodcing Hbf
● Patients did not need transfusions post therapy

The treatments were not bereft of side effects—all treatable so far. While the safety
and efficacy of CTX001 will be continually monitored, this milestone is a promising
ray of light for using gene editing for treating blood disorders and other genetic
diseases.

The continued progress of CRISPR-based therapeutics will require that researchers,

doctors, and drug manufacturers have reliable partners for gene therapy
development. Synthego is poised to support this effort at all stages of gene therapy
development from early discovery through clinical trial by delivering high quality
research-grade synthetic guide RNA as well as clinical-grade GMP reagent. In
addition to efficacy, Synthego is committed to the safe and accessible delivery of
CRISPR-based therapy.

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There are also other investigational therapies being developed using different gene
editing approaches. For instance, the groups of Dr. Matthew Porteus from Stanford
School of Medicine and Dr. Donald Kohn from UCLA are independently working on
SCD therapies through CRISPR-mediated repair of the associated mutation. A
non-CRISPR related approach from a group at Boston Children's Hospital has also
shown promising patient data. All in all, there is much to look forward to in the next
few years with next-generation therapeutics. Welcome to the era of gene therapy!

ABOUT THE AUTHOR

Meenakshi Prabhune, Ph.D.

Meenakshi Prabhune, a science writer and journalist, manages the Synthego blog
content. In her free time, one can find her traveling to new places or binge-watching
Netflix shows on her couch (both are equally probable). Follow Meenakshi on
Twitter (@minu_pr) for her latest updates.

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