FDA Document Raises Concerns Over a New Gene Editing Therapy

A cutting-edge cure or CRISPR catastrophe? That’s the question facing regulators.

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A cutting-edge cure or CRISPR catastrophe? That’s the question facing regulators as a revolutionary new gene editing treatment for sickle cell disease seeks approval.

The therapy, called exa-cel, is a new technology that would precisely edit a patient’s DNA. But in recent documents, the U.S. Food and Drug Administration has sounded the alarm about potential unintended edits that could have far-reaching health consequences.

The FDA is now getting external experts’ opinions on whether this CRISPR technology used by Vertex, a biopharmaceutical company, and CRISPR Therapeutics, a biotechnology company, is safe long-term.

Sickle Cell Disease and CRISPR-Cas9 Therapy

Sickle cell disease is a genetic disorder affecting hemoglobin, the oxygen-carrying molecule in red blood cells. Abnormal hemoglobin causes rigid, sickle-shaped cells that get stuck in blood vessels.

Symptoms include severe pain episodes, anemia, infections, delayed childhood growth, and complications like stroke and organ damage. Treatments such as blood transfusions can help manage the condition, but the only cure for some people is blood and bone marrow transplant. A significant number of sickle cell disease patients are unable to find a family member whose genetics closely match their own to serve as a suitable donor.

Exa-cel uses the CRISPR-Cas9 technology. Cas9 acts like scissors, cutting into DNA at a targeted spot guided by an RNA molecule. When Cas9 makes its cut, the cell tries to repair the DNA. Scientists can use this to intentionally delete or insert small bits of DNA code and edit genes.

This technology could allow doctors to fix genetic diseases by editing their corresponding locations in human DNA.

For the treatment specifically under review by the FDA, stem cells are extracted from the patient. The genetic mutations causing sickle cell disease are edited out using CRISPR technology. The edited stem cells are then injected back into the patient in a one-time infusion.

What Are FDA’s Specific Concerns?

The FDA has expressed concerns about the direct safety risks associated with the exa-cel treatment. Patients undergo intensive “conditioning” preparation, which includes chemotherapy that could lead to painful mouth sores and risk of infections, before treatment.

Another concern is the theoretical risk that while CRISPR tools edit the targeted gene in the stem cell’s DNA, they could cut the DNA in a different area of the genome as well.

“Since unintended edits can disrupt gene expression,” the FDA document wrote, it is critical that the specificity of exa-cel’s targeting component “be thoroughly screened to ensure off-target genome editing is minimized.”

The FDA noted issues with Vertex and CRISPR Therapeutics’ tests. The tests may not reflect genetic variations in sickle cell patients accurately, especially those with rare variants facing higher off-target edit risks.

Limited sickle cell donor cell availability also restricts comprehensive testing of the new technology.

“The key to this is safety,” Dr. Mark Walters, a pediatric hematologist-oncologist in California who has advised on the development of the treatment, said in a recent article published in Nature. “That’s the question that could really affect decision making, and the safety information is still quite limited.”

What Are the Dangers of DNA Manipulation?

Manipulating DNA holds promise in fields like medicine, agriculture, and research but also risks. Several potential dangers include:

Unintended Consequences

Changing DNA may impact other genes or health in unforeseen ways. The FDA expressed this concern about off-target effects of the proposed CRISPR sickle cell treatment.

Health Risks

Genetic modifications could lead to unexpected allergic reactions or other health problems.

Long-Term Effects

DNA changes may get passed to future generations, with unknown long-term effects on gene pools and biodiversity.

Ethical Concerns

Manipulating DNA, especially in humans, raises ethical issues. This includes concerns about creating designer babies, eugenics, and altering human traits, leading to ethical debates about the limits of such interventions.

Ecosystem Impact

In agriculture, modified DNA could affect other species and ecological balance. For instance, genetically modified organisms might outcompete or adversely affect native species.

Gene Flow

Modified genes could spread unintentionally by interbreeding with wild species.

Weaponization

Genetic manipulation may be misused to create biological weapons or pathogens, raising serious security concerns.

Regulatory Challenges

Overseeing DNA modification is difficult and risks misuse without adequate regulation.

To address these dangers, it’s crucial to proceed with caution, using robust safety protocols, rigorous testing, ethical guidelines, and transparent regulations in research and applications involving DNA manipulation. The goal should be to balance innovation and potential benefits with responsible and mindful practices.