CRISPR has seen a number of developments recently; 2020 was a good year for gene therapy. Medical professionals are excited by the improvements made and motivated to make further discoveries. In this article, we’ll be discussing past findings and trials, as well as the future of CRISPR in the treatment of rare diseases.

CRISPR and Blood Disorders

Rare blood disorders, such as beta thalassemia and sickle cell disease (SCD), have seen advances in treatment due to CRISPR technology. Both conditions are characterized by defective hemoglobin caused by altered genes.

When medical professionals were applying the gene editing technology to the treatment of these diseases, they did not try to directly fix the mutated genes. Instead, they used CRISPR technology to lift levels of fetal hemoglobin. This form of hemoglobin is seen only in fetuses in the womb, as children begin to make a different type of hemoglobin after they are born. It is also able to take the place of adult hemoglobin in SCD and beta thalassemia patients.

In order to do so, doctors will remove one’s blood stem cells and edit their genomes. Before putting these cells back into the patient, chemotherapy is used to get rid of any defective blood stem cells. Once they have settled into the bone marrow, they will create a new population of blood stem cells, all of which will produce fetal hemoglobin.

Current Trials

In February of 2019, medical professionals used an ex-vivo CRISPR-based gene therapy to treat a patient with beta thalassemia. This was the first-ever use of this type of therapy to treat a genetic disease. Since then, 12 more patients have received the treatment, and none have required transfusions in the months after.

It was not until July of 2019 that the first SCD patient received the therapy. Since then, she has shown remarkable progress. Further results include:

• All participants show normal or near-normal levels of hemoglobin in which 30% is fetal hemoglobin for SCD patients and 40% is fetal hemoglobin for beta thalassemia patients
• The administration of chemotherapy was the only cause of adverse effects
• Data from bone marrow samples demonstrate edited cells have successfully settled into the bone marrow

These trials are still running, led by Vertex Pharmaceuticals and CRISPR Therapeutics. As of now, they are actively recruiting participants throughout Europe, the United States, and Canada. Additionally, a trial will soon run that tests a treatment that repairs the mutations responsible for SCD. It will be led by UCLA, UC Berkeley, UCSF, and IGI researchers.

Looking Forward for Rare Blood Disorders

As of now, there is an increase in research on blood disorders. Medical professionals are utilizing both genetic and pharmaceutical approaches and seeing extremely positive results that propel further research.

Researchers note the importance of the trial mentioned above; participants must be followed for years afterward to fully understand the effects of the treatment. They also note that scalability, or making sure that the people who need the treatment have access, will be a problem moving forward. The complicity of the treatment paired with the high cost could restrict access to many. Further research and work to ensure access will be necessary.

About Sickle Cell Disease

Sickle cell disease (SCD) includes a group of disorders that are characterized by malformed red blood cells that look like sickles. The most common and severe form of this disease is sickle cell anemia. In sickle cell disease, deformed cells cause blockages and restricted blood flow as they get caught along the walls of blood vessels. This disease is caused by a mutation in the gene responsible for producing hemoglobin, which carries oxygen throughout the body. This gene is inherited in an autosomal recessive pattern, meaning both parents must pass down a copy to their child. Sickle cell disease is most common in people of African and Hispanic descent.

Symptoms of sickle cell disease include pain crisis, swelling of the hands and feet, and symptoms associated with anemia like fatigue, jaundice, and delayed growth. Adults tend to constantly feel the effects of this disease, but children usually only experience them during pain crisis. Regardless of age, damage usually occurs to the organs that are affected by the blocked blood flow. The most commonly damaged organs are the brain, eyes, spleen, liver, kidneys, lungs, heart, skin, joints, and bones. There is no cure for sickle cell disease. While some people qualify for bone marrow and blood transplants, not everyone is eligible for this procedure. Other forms of treatment are symptomatic and meant to prolong life.

About Beta Thalassemia

Beta thalassemia, like sickle cell disease, is a blood disease caused by an issue with hemoglobin, which is a deficiency in this case. This disease occurs as three different types, which are minor, intermedia, and major. These types relate to the severity of the symptoms, with people who have minor beta thalassemia often being asymptomatic and those who have major needing lifelong medical care. This disease is caused by a mutation on the hemoglobin beta gene.

Those who have a mutation on one copy of this gene often experience minor beta thalassemia while those who have mutations on both copies experience the intermedia or major types. The symptoms of this disease include fatigue, weakness, shortness of breath, dizziness, headaches, blood clots, pallor, and splenomegaly, which is an enlargement of the spleen. Treatments for beta thalassemia depend on the type one has. Those with major require blood transfusions, which can be harmful if they cause iron overloads. If the spleen is heavily affected, surgery can be done to correct it. There is also an FDA approved treatment called Thiotepa.

CRISPR And Cancer

The majority of work being done in gene therapy for cancer is focused on blood cancers, such as leukemia or lymphoma. However, there has been research and clinical trials conducted on a gene therapy for lung cancer as well.

When utilizing CRISPR for the treatment of cancer, researchers typically engineer the T-cells, an essential part of the immune system, to attack cancer cells. As cancer cells typically mask themselves as ‘safe’ for the body by hiding themselves in molecular safety signals, this therapy creates a higher chance of killing cancer cells.

In order to conduct this treatment, doctors must take a patient’s T-cells and edit them in the lab. Afterward, they will replace the cells via IV.

Current Trials

A Chinese clinical trial that began in 2016 was the first to treat a patient with lung cancer with CRISPR gene therapy. In addition to this study, an American trial tested the same thing. They are now completed, but other trials are still ongoing.

Looking deeper into the Chinese trial, we see that twelve patients, all of whom had non-small cell lung cancer, were treated with PD-1 edited T-cells. Results show:

• On-target effects were more common than off-target effects
• The treatment was safe, and adverse effects were acceptable
• The desired edit was present in 6% of T-cells before they were infused back into the patient
• 11 of the 12 patients were found to have edited T-cells in their bodies two months after infusion

Turning towards the American trial, it combined PD-1 and CAR-T cell approaches to edit three genes. The first phase of this study was completed in February of 2020 by UPenn and the Parker Institute. A patient with advanced myeloma and another with metastatic sarcoma participated, and findings include:

• Edited T-cells settled into the bone marrow and remained at stable levels for nine months
• Treatment was safe with acceptable side effects
• While off-target effects were observed at a low frequency, researchers did see that unwanted changes at the target site were common
• T-cells were able to target and infiltrate tumors, as shown through tumor biopsies

While neither of these treatments offers a complete cure, they are tolerable, safe, and demonstrate promising results.

Looking Forward for Cancer

CAR-T therapies have already been approved by the FDA, along with PD-1 pathways without genome editing. This demonstrates that CRISPR gene editing is a viable option that deserves further development. Hopefully, future research leads to improvements and more treatment options for rare disease patients.

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