UC launches gene therapy trial for treatment of sickle cell disease

CRISPR editing aims to correct defect that causes blood illness

“We are motivated to work toward a cure that can be accessible and affordable to patients worldwide. The launch of this trial is an essential first step on that path.”

— UC Berkeley’s Jennifer Doudna, clinical diagnostics laboratory leader at the Innovative Genome Institute

A team of University of California scientists are launching a first-ever human study of a powerful new gene-editing technique to fix the bad gene that causes sickle cell disease, offering the promise of a cure for the devastating blood illness.

On Tuesday, researchers announced that they have received U.S. Food and Drug Administration approval to test the approach, using a technique called CRISPRCas9, at UCSF Benioff Children’s Hospital Oakland and

UCLA’s Broad Stem Cell Research Center.

“Our goal is to be able to deliver a safe and effective therapy that we can administer as soon as we know the diagnosis — and spare those children and young adults all the complications of this disorder,” said Dr. Mark Walters, a professor of pediatrics at UC San Francisco and principal investigator of the project.

For 65 years, scientists have known the cause of sickle cell disease but have been unable to cure it without a bone marrow transplant. By fixing the underlying genetic problem, the new research buoys hopes for thousands of suffering people — and opens up the possibility of treating other simple inherited disorders.

An estimated 6,200 Californians are living with the disease. It primarily afflicts people of African descent; about 40% are under the age of 18. It is caused by a single gene mutation that makes red blood cells warp and clog arteries, causing excruciating pain and often death. Available treatments are limited, involving regular transfusions.

The study, which will take four years, plans to enroll its first patients this fall. It will start with six adult patients between the ages of 18 and 35 who are very sick. Once proven safe and effective, it will be tested in three younger and healthier patients.

A similar trial is planned at Stanford and will begin recruiting patients as soon as the university completes its review, according to Dr. Matthew Porteus, associate professor of pediatrics.

The new research efforts

enlist CRISPR-Cas9 as a microscopic scalpel, performing genomic surgery with precision and efficiency.

CRISPR — which stands for “clustered regularly interspaced short palindromic repeats,” or clusters of brief DNA sequences that read similarly forward and backward — works like the search-and-replace function of a computer.

It is transforming research, with scientists using it to try to fix the genes that cause muscular dystrophy, hereditary blindness, Huntington’s disease, Sanfilippo syndrome and cystic fibrosis.

An estimated 10,000 human

diseases are caused by a single gene defect that could potentially be corrected by CRISPR, according to Dr. Maria Grazia Roncarolo, co-director of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine.

For sickle cell disease, the big unknown is how to best deliver CRISPR’s genetic fix.

While trials at other universities have successfully added extra copies of the healthy gene, or knocked out the bad gene, the new trial is a gene “knock-in.” It is very targeted — replacing the defective gene with a repaired version.

The UC scientists will do that by harvesting some of the stem cells, which generate blood cells, in the bone marrow of a patient.

In the lab, they will excise

the bad region of the patient’s beta-globin gene from the stem cells, using CRISPR, then introduce a good genetic segment. This part of the project will be conducted in a Los Angelesbased manufacturing facility at UCLA’s Broad Stem Cell Research Center, led by Dr. Donald Kohn.

The repaired cells will incubate for several days, then get shipped to Oakland. Meanwhile, the patient would undergo intensive chemotherapy to kill the remaining sick stem cells and make room for new ones.

The corrected stem cells will be infused into the patient. Once in place, they should produce healthy cells to replace the sick cells — so the patient heals.

In the lab, not every bad blood cell must be repaired.

The team is currently correcting about 20% to 25% of the genes. The goal is to boost efficiency and correct at least 40% of the blood stem cells.

“It will hopefully reconstitute a blood system that no longer makes a significant number of sickle red blood cells,” said Walters. “The sickle mutation is gone and the regular healthy hemoglobin is made in its stead.”

The treatment poses significant risk. High-dose chemotherapy can cause short-term side effects. And it’s dangerous; without a strong immune system, a patient can develop deadly infections, or leukemia.

The trial will be deemed successful if it meets two goals: reconstituting a healthy blood system and reducing a patient’s pain.

The analytical support for the trial — counting the number of reconstituted cells, studying cells’ biology and behavior and monitoring patient well-being — will be conducted by the Bay Area’s Innovative Genome Institute, a joint research collaboration between UC Berkeley and UC San Francisco.

“We are motivated to work toward a cure that can be accessible and affordable to patients worldwide,” said UC Berkeley’s Jennifer Doudna, who leads the IGI’s clinical diagnostics laboratory, and along with France’s Emmanuelle Charpentier earned the 2020 Nobel Prize in chemistry for the CRISPR discovery. “The launch of this trial is an essential first step on that path.”

Each experimental treatment

is extraordinarily expensive, costing between $500,000 to $750,000 per patient.

The team is now planning how to cut costs and boost efficiency by manufacturing the cells more cheaply — or even devising a way to safely deliver the CRISPR technique directly into the body, without removing stem cells or destroying the bone marrow. Someday, they hope to offer their treatment to poorer parts of the world.

“The costs will come down, as we gain more experience and identify areas to economize,” said Walters.

“While this is the first step, it won’t be the last,” he said. “Our dream is to make this broadly accessible by making it easier to treat patients.”