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by Jennifer Maxon R.N. Medically reviewed by Dr. C.H. Weaver M.D. 12/2020

Although various forms of genetic manipulation have been around for decades, the actual implementation of precision gene editing in the treatment of a living person is a first.

For the past few years, researchers have been brimming with enthusiasm as the fairly new gene-editing technique, referred to as CRISPR, which stands for clustered regularly interspaced short palindromic repeats, has swiftly infiltrated research labs worldwide, becoming a game changer in the field of genetics. Meanwhile international scientific and bioethics communities are closely monitoring the “CRISPR craze” to enforce the adopted ethical standards to which all scientists are to adhere.

Patients treated with a CRISPR-based gene-editing therapy for the inherited blood disorders sickle cell disease and beta-thalassemia have shown a sustained response with manageable side effects, according to interim results from two clinical trials reported at the December 2020 American Society of Hematology Annual Meeting.

Sickle cell disease and beta-thalassemia are caused by genetic mutations that produce defective forms of hemoglobin the essential oxygen carrying protein needed by red blood cells to nourish the body.

The goal of CRISPR therapy is to functionally cure both disorders by increasing the production of fetal hemoglobin — the healthy, oxygen-carrying form of hemoglobin that is produced during fetal development but normally shuts down soon after birth. Higher levels of fetal hemoglobin in people with sickle cell disease and beta-thalassemia are associated with reduced symptoms and improved outcomes.

The data released at ASH was from Vertex Pharmaceuticals and CRISPR Therapeutics who are jointly developing the CTX-001 gene-editing treatment.

The Vertex/CRISPR clinical trial, called CLIMB-111, has enrolled 13 patients with beta-thalassemia, seven of whom have been followed long enough to be evaluable for response. All seven patients remain transfusion free, with follow up ranging from three to 18 months. Five of the seven patients have been followed for six months, during which their total hemoglobin levels were in the normal range — nearly all of it consisting of the fetal hemoglobin produced by the CRISPR’d cells.

The second study called CLIMB-121, reported the outcomes of the first three patients with sickle cell disease. Before treatment with CTX-001 these patients were experiencing an average of six vaso-occlusive pain crises a year. After treatment, all three have been crisis-free, with follow-up times ranging from three to 15 months.

Manipulating the Genetic Code

The idea of purposefully manipulating a human’s genetic code tends to evoke an emotional response in almost everyone, whether it stems from intrigue, hope, fear, or a combination thereof. There also exists an underlying vague apprehension in many, based on the notion that humans tinkering with life-altering genetic codes just because they can sets us on a path through uncharted territory.

Conversely, parents of a terminally ill child with no further treatment options, or individuals with an inherited disease that is robbing them of their independence and dignity, or even those who watch a loved one suffer and are desperate for their relief may feel a dire sense of urgency to expedite the availability of therapy using genetics, as it represents a last bit of real hope for their situation.

It is against the backdrop of all of these questions and emotions that scientists are forging a path to learn more about how genetic manipulation will factor into our health as we move forward.

What Is Gene Editing?

Gene editing, also called genomic editing, is a type of genetic engineering in which very specific and targeted pieces of a gene are altered with precision.

Every living organism’s genetic code has a primary component known as DNA. DNA is essentially composed of four different molecules called nucleic acids; these nucleic acids occur in different sequences—for a length of an approximate 6 billion in consecutive order.

A gene is a piece of DNA that may comprise a few or up to hundreds of thousands of nucleic acids. It is the differences in the DNA sequences that create all the variances among individuals and organisms—or the differences between a healthy cell and a cancer cell.

During a gene-editing process, very specific DNA sequences can be removed and specific new DNA sequences can be inserted into a gene at a precise location. The newly inserted DNA sequence becomes part of the organism’s genetic code and has the potential to be passed on to the organism’s offspring and future generations.

An important distinction of gene editing that sets it apart from other types of genetic engineering is its precision, by which very specific and targeted DNA sequences can be removed and added. Furthermore, unlike different genetic-engineering methods, such as those often used in the production of genetically modified products, gene editing does not include the introduction of foreign genetic material from a different species or organism.

What Is the CRISPR Technique?

The CRISPR technique possesses the traits needed to launch gene editing into a real-world setting: fast results, efficiency, precision, affordability, and reproducibility. The older gene-editing methods were time-consuming and expensive and required many more resources than CRISPR does.

The CRISPR technique basically involves a two-prong strategy. First researchers determine very specific DNA sequences that they wish to target (i.e., a sequence associated with the development of cancer). Next a preprogrammed microscopic “guide” is used to search for the precise DNA sequence slated for manipulation. Once the guide finds the particular DNA sequence, it communicates to a different protein, which acts like a surgeon’s scalpel to cut out the sequence. A new sequence of DNA is then placed where the old sequence once resided.

The microscopic guides and “scalpels” are engineered in a laboratory but are made of biological materials that already exist in human cells, circumventing the introduction of foreign material. They are simply injected into the patient or subject in the same manner in which a vaccination is given, and they work together in the body to complete their task. As the CRISPR method evolves, it continues to be refined and is providing even greater precision with faster results—while becoming less expensive. In fact, any scientist with basic skills and a few hundred dollars can implement CRISPR. Orders for specific guides can be placed online and received within a few days, as well as an order of “designer” guides to find newly discovered sequences.

Clinically What are the Steps?

  • Blood-producing stem cells are collected from patients.
  • The stem cells are genetically edited using CRISPR/Cas9 so they will make fetal hemoglobin.
  • Patients undergo “preparative” treatment with busulfan chemotherapy to eradicated mutation-carrying stem cells in their bone marrow.
  • CRISPR-edited cells are infused back into the patient which grow and produce blood cells in the bone marrow.

What Does This Mean for Cancer?

While the initial results using CRISPR are promising for the inherited blood disorders sickle cell disease and beta-thalassemia, precise gene-editing therapy is also being evaluated for treating people with cancer**.** Immune cells genetically edited using CRISPR and infused back into patients with multiple myeloma and sarcoma were reported to be safe and represent a feasible approach to cancer treatment according to results of a clinical trial presented at the 2019 American Society of Hematology Annual Meeting.

Doctors first removed the most immunologically active cells against cancer from a patient’s blood and then engineered them to be even better cancer fighters before infusing the cells back into the patients.

  • Researchers removed T cells from the blood of three patients and then used CRISPR technology to remove three genes from the cells, including T-cell receptors and PD-1.
  • They then used a lentivirus to insert an affinity-enhanced T-cell receptor directing the edited cells to target a specific antigen on cancer cells.
  • The patients received the edited cells in a single infusion following a short chemotherapy course.
  • The CRISPR-edited cells expanded in number and survived in all three patients without causing serious side effects.

CRISPR is different than CART-cell therapy

CAR T technology allows the insertion of genetic material into cells and puts a primary antigen receptor warhead on the cell surface. This has been a very successful treatment for patients with leukemia and lymphoma.

CRISPR editing is an attempt to further enhance the activity of these cells. In addition to inserting the gene, researchers used CRISPR to remove three other genes. By removing two genes that coded for the T-cell receptors it may allow the edited cells to better target tumors, because there is no competition. Researches also remove the PD-1 gene, so the cells could not check immune activity.

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CAR T-cell activity is limited because you are using the cancer patients own cells, you have to harvest them and manufacture them for several weeks.

A problem with using someone else’s cells is that they could be rejected by the patient’s body or cause side effects. If CRISPR can be used to remove the genes on somebody else’s T cells and these cells could be manufactured in quantity, they could be kept in storage for use whenever a patient needed them.

The future in the treatment and prevention of cancer using the CRISPR method holds immeasurable promise. Researchers are hopeful that CRISPR will allow for the correction of very specific DNA sequences that are known to make a person susceptible to developing cancer, ultimately eliminating the risk of cancer for that person in their lifetime.

Or, if a person does get cancer, researchers anticipate that in the future they will be able to determine precisely which DNA sequences need to be eliminated, corrected, or inserted to shut down the growth of existing cancer cells and cure the disease. Due to the precision of CRISPR, the hope is that a cure can be obtained without the toxic side effects associated with the standard types of therapy available today.

Furthermore, researchers believe that the CRISPR method will allow them to determine exactly which types of therapy will work for each patient according to the cancer’s genetic traits, or they will be able to manipulate cancer cells to respond to certain types of therapy with pinpoint precision.

The initial clinical trials for gene editing will include patients with advanced types of cancers for which there are most likely no other available treatment options. From there, if gene editing proves safe, advancements into further trials to evaluate its effectiveness will continue, followed by a comparison of effectiveness against standard therapies.

As the CRISPR Story Unfolds

As with all new advancements in human history, the way in which gene editing will shape the future remains unknown. Unlike many other milestones, however, gene editing encompasses an element that requires caution, as altering genetic code will have repercussions for generations. Fortunately, researchers have stated that the possibility of reversing an error made with CRISPR is plausible, as they could, in theory, remove any DNA sequences that had been mistakenly inserted and correct the mistake.

Nonetheless the progression of gene editing in clinical trials will not be hurried. The ethics and scientific committees are strictly enforcing guidelines, and researchers, to the best of their ability, are allowing no room for error in their work.

All of this taken into consideration, CRISPR has undoubtedly launched a new era for the way in which diseases, including cancer, will be treated. Considering the days of nothing more than surgery, chemotherapy, and radiation as options for cancer, finding a cure suddenly seems as though it could someday become a reality.

Bench Research Paved The Way...

In 2018 the Food and Drug Administration approved the first cellular immunotherapies to treat cancer. These therapies involve collecting a patient’s own immune cells — called T cells — and supercharging them to home in on and attack specific blood cancers, such as hard-to-treat acute lymphoblastic leukemia and non-Hodgkin lymphoma.

But so far, these T cell immunotherapies — called CAR-T cells — can’t be used if the T cells themselves are cancerous. Even though supercharged T cells can kill cancerous T cells, they also can kill each other because they resemble one another so closely.

Scientists at Washington University School of Medicine in St. Louis now have used the gene-editing technology CRISPR to engineer human T cells that can attack human T cell cancers without succumbing to friendly fire.

The study evaluating the approach in mice appears online in the journal Leukemia.

The researchers also engineered the T cells so any donor’s T cells could be used. A “matched” donor with similar immunity is not required and neither are the patient’s own T cells, which is important for the obvious reason: Many of the patient’s own T cells are cancerous.

“Cancerous T cells and healthy T cells have exactly the same protein — CD7 — on their surfaces,” said senior author John F. DiPersio MD PhD, the Virginia E. and Sam J. Golman Professor of Medicine in Oncology.

DiPersio’s team first generated a novel CAR-T strategy targeting CD7, allowing for the targeting and killing of all cells with CD7 on the surface.

“But if we program T cells to target CD7, they would attack the cancerous cells and each other, thus undermining this approach,” DiPersio said. “To prevent this T cell fratricide, we used CRISPR/Cas9 gene editing to remove CD7 from healthy T cells, so they no longer carry the target.”

DiPersio, who treats patients at Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital, and his colleagues also used CRISPR gene editing to simultaneously eliminate the therapeutic T cells’ ability to see healthy tissues as foreign.

To do this, they genetically deleted the T cell receptor alpha (TCRa) subunit. This way, T cells from any normal donor can be used without risk of life-threatening toxicities such as graft-versus-host disease, in which T cells attack the organs of the recipient, sometimes resulting in death. This new approach also may have broad implications for the CAR-T field, allowing for use of therapeutic T cells from any healthy donor. Healthy T cells could be collected in advance and stored for any patient with a relapsed T cell malignancy.

“We have genetically modified these T cells so they are unable to cause graft-versus-host disease but can still kill cancerous cells,” said first author Matthew L. Cooper, PhD, an instructor in medicine. “One additional benefit of this approach is that a patient could receive this therapy much more quickly after diagnosis. We wouldn’t need to harvest the patient’s own T cells and then modify them, which takes time. We also wouldn’t have to find a matched donor. We could collect T cells from any healthy donor and have the gene-edited T cells ready in advance, a strategy termed ‘off-the-shelf’ CAR-T cell therapy.”

The researchers demonstrated that this approach is effective in mice with T cell acute lymphoblastic leukemia (T-ALL) taken from patients. Mice treated with the gene-edited T cells targeted to CD7 survived 65 days, compared with 31 days in a comparison group that received engineered T cells targeting a different protein. The researchers also found no evidence of graft-versus host disease in mice that received T cells lacking the molecular machinery that sees healthy tissues as foreign. They also found that the therapeutic T cells remained in the blood for at least six weeks after the initial injection, suggesting it could ramp up again to kill cancerous T cells if they return.

“T cell malignancies represent a class of devastating blood cancers with high rates of relapse and death in children and adults with the disease,” Cooper said. “In an effort to develop the first clinically viable targeted therapy for this type of cancer, we are scaling up the manufacturing of our gene-edited CAR-T cells for clinical trials, which we hope to complete at Siteman Cancer Center.”


  1. Choi et. al. An ‘off-the-shelf’ fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. February 2018.
  2. Stadtmauer EA, et al. Abstract 49. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.

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