Crispr’s Next Frontier: Treating Common Conditions

In the next decade, Crispr-Cas9 and other new gene-editing techniques may protect the health not only of Ms. Wilemon and others with familial hypercholesterolemia but millions of people with a range of conditions, including chronic pain and diabetes. Rather than take drugs for years or even decades, for example, at-risk people might be able to protect themselves with a one-and-done Crispr therapy.

It has been a year of profound change that is still transforming all aspects of society. Science has brought revolutionary technologies from the lab into people’s daily lives. Covid-19 vaccines and Crispr gene editors both built on decades of research into RNA, a crucial molecule in cells. During the pandemic, the flourishing of both seemed to signal a new era in genetic medicine.

“We need to think about what it will mean for all of us to live in a gene-edited world,” says Fyodor Urnov, scientific director of technology and translation at the Innovative Genomics Institute at the University of California, Berkeley.

Last year, two scientists won the Nobel Prize for their work on Crispr-Cas9, which can be used to alter disease-causing genes. The prize came eight years after Drs.

Jennifer Doudna

and

Emmanuelle Charpentier

published a landmark paper demonstrating how Crispr-Cas9—which bacteria use to defend themselves against viruses—could be adapted to create a tool to edit DNA in animals, plants and people.

Scientists reported last December that gene-edited cells curbed severe pain and other symptoms in a small number of patients with sickle cell disease and beta-thalassemia, two rare, inherited blood disorders.

Verve Therapeutics, a Cambridge, Mass.-based startup, presented animal research in 2020 showing that a Crispr-based therapy for cardiovascular disease reduced levels of LDL, or “bad” cholesterol, by an average of 61%.

Crispr Therapeutics,

a Swiss company, and a partner plan to test a Crispr therapy for diabetes: An under-the-skin implant containing Crispr-edited cells that will deliver insulin, with the goal of eliminating injections and regular testing of glucose levels.

The original version of Crispr—what Dr. Urnov calls “Crispr 1.0”—cuts both strands of the double-stranded DNA molecule. Breaking both strands can lead to unintended edits and potentially deleterious health effects.

New versions of Crispr may allow more precise edits. A “Crispr 2.0” technique called base editing, for example, can change DNA without cutting its strands.

In the case of heart disease, scientists are using Crispr in an attempt to turn off the disease-causing PCSK9 gene in the liver. By turning off the gene, people are able to maintain very low LDL levels and are protected against heart disease. A clinical trial of PCSK9 editing now in the works will likely start with people with severe cardiovascular risk but eventually could be applied more broadly.

“This is the same path statins followed,” Dr. Urnov says of the familiar cholesterol-lowering drugs. “They were developed for people with severe disease. Now, many people take them for prevention.”

At a meeting earlier this year of the Familial Hypercholesterolemia Foundation, families living with the disease heard a scientific presentation about how Verve Therapeutics plans to use a base-editing technique for cardiovascular disease.

The technique involves infusing minute balls containing the Crispr editing machinery into the bloodstream. These so-called lipid nanoparticles make their way to the liver. There they break up and release the editing machinery, which homes in on and edits the PCSK9 gene—creating the version that stops it from making a cholesterol-raising protein. In studies on monkeys, the animals exhibited low levels of LDL cholesterol even six months after treatment, raising hopes that the edits could last a lifetime.

“We think the data in monkeys will translate well into humans,” says Verve Therapeutics co-founder Sekar Kathiresan. The company wants to launch a clinical trial of the experimental treatment in 2022, first in familial hypercholesterolemia patients who have suffered a heart attack. The company eventually hopes to test the treatment in heart attack sufferers who don’t have familial hypercholesterolemia.

If the therapy proves to be safe and effective as a treatment, the next stage will be to explore its use for heart attack prevention. “This could be a preventive therapy for all who are at risk for heart attacks,” Dr. Kathiresan says.

But financial and logistical as well as scientific hurdles remain. Crispr therapies will be costly at first and may not be available at all hospitals. Scientists don’t know how to routinely and safely deliver Crispr editing for all diseases.

Before participating in a Crispr trial, Victoria Gray, 35, a sickle cell patient from Forest, Miss., suffered severe pain that put her in the hospital more than six times a year. “My life was full of pain,” she says. Now, more than 18 months later, she says she hasn’t suffered a pain crisis or needed a blood transfusion. “I call myself cured,” she says.

Ms. Gray’s doctor, Haydar Frangoul, acknowledges the benefits of Crispr but says it is too soon to use the word cure. It is unclear whether gene edits will last a lifetime. Dr. Frangoul says problems caused by gene editing might take decades to show up—one reason the patients in the trial will be followed for 15 years.

“We showed Crispr gene editing works in humans,” Dr. Frangoul says. “We made a crack in the door. The crack is getting wider.”

Ms. Wilemon, who started the foundation after learning that her oldest daughter had high LDL cholesterol levels, says she knows it is still early days for Crispr. But she’s optimistic about what deeper understanding of genetics and a technology like Crispr might mean for her child, who is now 14. In such a future, Ms. Wilemon says, “Maybe I won’t have to worry about the trajectory of her life.”

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Write to Amy Dockser Marcus at [email protected]