Pioneering the world’s first CRISPR medicine for sickle cell disease

When Vijay Sankaran was an MD-PhD student at Harvard Medical School in the mid-2000s, one of his first clinical encounters was with a 24-year-old patient whose sickle cell disease left them with almost weekly pain episodes.

“The encounter made me wonder, couldn’t we do more for these patients?” said Sankaran, who is now the HMS Jan Ellen Paradise, MD Professor of Pediatrics at Boston Children’s Hospital.

As a budding hematologist, Sankaran knew all too well that people with sickle cell disease — marked by malformed, sickle-shaped red blood cells that can aggregate and block small vessels — experience excruciating pain crises, tissue and organ damage, and shortened life expectancy.

He also understood that the only treatment available at the time was hydroxyurea, which reduces sickling but isn’t effective in all patients and can cause side effects. The only chance at a cure was to undergo a bone marrow transplant, available to only a small percentage of patients because it carries significant risks and requires a well-matched donor.

Sankaran’s rotations through the hematology clinic made him want to change the story of the disease, both at the bedside as a soon-to-be physician and by joining the laboratory of HMS alumnus Stuart H. Orkin, the HMS David G. Nathan Distinguished Professor of Pediatrics at Boston Children’s and Dana-Farber Cancer Institute.

In 2008, Orkin, Sankaran, and colleagues achieved their vision by identifying a new therapeutic target for sickle cell disease.

In December 2023, through the development efforts of CRISPR Therapeutics and Vertex Pharmaceuticals, their decades-long endeavor reached fruition in the form of a new treatment, CASGEVY, approved by the U.S. Food and Drug Administration.

The decision has ushered in a new era for sickle cell disease treatment — and marked the world’s first approval of a medicine based on CRISPR/Cas9 gene-editing technology.

A foundation for the first gene-editing medicine

By the time Sankaran joined the federally supported Orkin Lab, Orkin had been illuminating the underlying mechanisms of red blood cell development and function and related hematological disorders for decades.

“Over the last 40 years, Stu has been a pioneer,” said HMS alumnus David Altshuler, executive vice president and chief scientific officer at Vertex and senior lecturer on genetics, part-time, at HMS, who oversaw the development of CASGEVY. “Through his work, we’ve come to understand how red blood cells work, how they develop in the body, and, particularly, how mutations lead to sickle cell disease.”

Sickle cell disease stems from a mutation in the gene that makes hemoglobin, the protein in red blood cells that carries oxygen throughout the body. Orkin’s team and others revealed that hemoglobin has two forms — fetal and adult — and that only the adult form is affected by sickle cell mutations, while the fetal form functions normally. However, shortly after birth, fetal hemoglobin production is turned off in the body, while adult hemoglobin production takes over.

Orkin had been investigating whether it was possible to switch fetal hemoglobin back on to treat sickle cell disease, but progress had stalled. Then, with help from Sankaran, patient samples from the National Institutes of Health, and a team in Sardinia, Italy, advances in genome-wide association studies revealed the gene that would hold the ticket: BCL11A.

Sankaran and Orkin showed that BCL11A suppresses production of fetal hemoglobin. Their landmark publication in Science kicked off a new era for sickle cell disease research.

Just three years later, in 2011, Orkin and others in his group showed that removing BCL11A from developing red blood cells in a mouse model of sickle cell disease turned on fetal hemoglobin production and cured the mice. This laid the foundation for clinical trials.

In 2013, another hematology fellow who joined the Orkin laboratory, Daniel Bauer — now the HMS Donald S. Fredrickson, MD Associate Professor of Pediatrics at Boston Children’s — identified a DNA sequence in BCL11A that, when removed, drastically reduced the gene’s activity.

Then CRISPR/Cas9 gene-editing technology swept onto the scene, and Bauer, Orkin, and colleagues identified a single DNA cut that could impair BCL11A activity.

But a steep climb remained to transform this discovery into a safe and effective gene therapy for patients. Appreciating both the difficulty and the importance of such work, the researchers and their home institutions made the intellectual property available to companies through nonexclusive licensing.

Bringing the first genetic medicines to patients

Altshuler decided in 2015 to leave academia after 25 years, including 15 years as HMS professor of genetics and of medicine, to join Vertex full-time. He was motivated to contribute to the paradigm shift happening in genetic medicine — particularly the translation of biological insights into therapies for patients.

“My mind moved on from discovery to ‘how are we going to make therapies?’” he explained. “We were looking for new programs where we could make a transformative medicine for people with a serious disease.”

Altshuler had followed the work of the Orkin Lab for many years, and he had taught Sankaran in the classroom. On day one at Vertex, he knew that he wanted to work on BCL11A.

We were looking for new programs where we could make a transformative medicine for people with a serious disease."

David Altshuler, Vertex executive vice president and chief scientific officer; HMS senior lecturer on genetics, part-time

Over the next nine years, Altshuler oversaw further research and development of the experimental therapy through a plethora of preclinical and clinical studies led by CRISPR Therapeutics and Vertex.

In clinical trials, the therapy eliminated small-vessel blockages, known as vaso-occlusive or sickle cell crises, for virtually all patients.

Today, CASGEVY is approved for use in patients with sickle cell disease in the United States and multiple countries in Europe and the Middle East.

“It’s an amazing gift to have been able to play a role in such a thing,” said Altshuler.

The tale continues

Vertex is working to secure approvals in additional countries, and it takes time after such approvals for treatments to actually become available to patients. Altshuler estimates it will take another 5 to 10 years to provide maximum access.

Plus, researchers including Orkin, Sankaran, and those at Vertex continue to conduct research to make sickle cell treatment more effective, more efficient, and appropriate for even more patients. Right now, only a subset of patients qualify for CASGEVY, mainly because it requires a bone marrow transplant and access to well-resourced health care facilities. Access is also limited by treatment cost. The current treatment also does not reverse permanent damage previously wrought on the body by the disease.

“It’s the beginning of a long journey,” said Altshuler. “We will keep working to make better therapies until we can help all patients with this disease around the world.”

For his part, Sankaran has been thrilled to see a new option for patients and to be part of what he hopes is a growing trend of academia-industry partnerships that shorten the time and raise the success rates of bringing lab discoveries to the clinic.

“I’m excited about what’s ahead, because as somebody who spends their time largely in the laboratory, I see things happening — fundamental discoveries — that hopefully will also start to impact the kind of therapies that industry can test in patients,” he said.

Three key players share the story of how fundamental discoveries in the laboratory became a first-of-its-kind therapy that promises to have a monumental impact on sickle cell disease patients around the world. Video Credit: Rick Groleau