Dec. 8 was a historic day for the sickle cell community and CRISPR technology, as the U.S. Food and Drug Administration (FDA) approved two milestone treatments: Casgevy, made by Vertex Pharmaceuticals, and Lyfgenia, made by bluebird bio.
Casgevy (exa-cel) is the first FDA-approved medicine developed through CRISPR technology, discovered just over a decade ago. Since that discovery, scientists have said CRISPR will revolutionize medicine – and it appears that revolution has begun.
Both Casgevy and Lyfgenia (also known as lovo-cel and made with a different genetic modification technique), are the first FDA-approved cell-based gene therapies for the treatment of sickle cell disease (SCD) in patients 12 years and older.
“I am thrilled to see sickle cell disease patients have more options, and more on the way!” said Dr. Ted W. Love, Chair of the Biotechnology Innovation Organization (BIO) and founder of another biotech addressing SCD, Global Blood Therapeutics.
“Sickle cell disease is a rare, debilitating and life-threatening blood disorder with significant unmet need, and we are excited to advance the field, especially for individuals whose lives have been severely disrupted by the disease by approving two cell-based gene therapies today,” said Nicole Verdun, M.D., Director of the Office of Therapeutic Products at the FDA’s Center for Biologics Evaluation and Research.
“Gene therapy holds the promise of delivering more targeted and effective treatments, especially for individuals with rare diseases where the current treatment options are limited.”
Vertex Pharmaceuticals and bluebird bio are both BIO members.
How these gene therapies work
Sickle cell disease affects about 100,000 people in the United States and disproportionately affects the Black community.
The inherited blood disorder results in a mutation in hemoglobin, a protein found in red blood cells that delivers oxygen to the body’s tissues. The mutation causes red blood cells to develop their characteristic crescent or “sickle” shape, which restricts the flow of blood in the body’s vascular system and limits oxygen delivery to tissues. This, in turn, leads to severe pain and organ damage. The recurrence of these events can lead to life-threatening disabilities and/or early death.
While both therapies are gene-based, bluebird’s Lyfgenia employs a previously used lentiviral vector (gene delivery vehicle) for genetic modification. This method takes a patient’s blood stem cells and genetically modifies them to produce HbAT87Q, a gene-therapy-derived hemoglobin that functions similarly to hemoglobin A (normal adult hemoglobin). These newly modified red blood cells have a lower risk of sickling and occluding blood flow. These modified stem cells are then delivered to the patient, the FDA explains.
Vertex’s Casgevy, on the other hand, involves taking a patient’s hematopoietic (blood) stem cells and modifying them via CRISPR-Cas9. The modified blood stem cells are transplanted back into the patient, where they attach and then multiply within the bone marrow. This increases the production of fetal hemoglobin (HbF), a type of hemoglobin that facilitates oxygen delivery. This therapy allows the levels of HbF to increase in patients and prevent the sickling of red blood cells in the future.
Life-changing therapies fulfilling an unmet need
“Sickle cell disease is one of those diseases that we talk about when we talk about those that have very high unmet medical needs,” explained Julianne Bruno, Senior Vice President at CRISPR Therapeutics, on the I am BIO podcast in April 2023.
Bruno has been working on developing the exa-cel program, an ex vivo gene therapy that eventually became Casgevy.
“Despite the fact that patients suffering from sickle cell disease have significantly earlier mortality, and have incredibly painful crises and very disruptive, ongoing symptoms, even in spite of all of that, there hasn’t been a lot of innovation for treatments for these patients,” she said.
For patients in the exa-cel (Casgevy) clinical trials, the results were life-changing. “If you look at the most recent data update for exa-cel, the patients that have been treated with it have had a cessation of those pain crises going out past three years now, which is really remarkable,” Bruno said.
In an op-ed published by MIT Technology Review prior to the FDA’s approval, a participant in the exa-cel (Casgevy) clinical trials, Jimi Olaghere, wrote: “After I received exa-cel, I started to experience things I had only dreamt of: boundless energy and the ability to recover by merely sleeping. My physical symptoms—including a yellowish tint in my eyes caused by the rapid breakdown of malfunctioning red blood cells—virtually disappeared overnight. Most significantly, I gained the confidence that sickle cell disease won’t take me away from my family, and a sense of control over my own destiny.”
Olaghere testified in favor of the treatment to the FDA’s advisory group as it met to evaluate the evidence.
What is CRISPR?
The approval of Casgevy paves the way for further advancements in CRISPR-Cas9 technology and treatments.
However, despite the technology’s potential, CRISPR-Cas9 is often misunderstood.
“An important misconception about CRISPR, in my mind, is that the technology is more advanced than it actually is,” Benjamin Oakes, co-founder, President, and CEO of Scribe Therapeutics, said on the I am BIO podcast.
CRISPR-Cas9 can be directed to cut DNA in targeted areas, enabling the ability to accurately edit (remove, add, or replace) DNA where it was cut,” explained the FDA.
But what exactly does that mean? Are we now able to simply go and tinker with our DNA as we like?
Genome editing is more complicated than “that control-F function in a Word document,” according to Oakes. We act as if we could just search for “the word that’s misspelled, and we can go change that—well, that’s not true.”
“In this example, from the perspective of what CRISPR technology does, when it creates a double-stranded DNA break, it usually creates essentially a mutation at the site of that double-strand break,” Oakes continued. “As researchers and medical professionals, we can utilize that mutation to accomplish a goal, for example, turning on fetal hemoglobin to treat sickle cell disease. But the reality is not yet that we have a piece of the genome that looks like X, and we want it to look exactly like Y, and we can make that happen 100% of the time, every time, because even if we can make that happen, it’s a probabilistic thing. So, it might happen 20% of the time, and then the other 80% of the time, I get something else.”
“And this is why we still do believe deeply that there is a lot of room for improvement in CRISPR technology and why we’re dedicated to engineering these CRISPR tools to be better,” he noted.
‘The age of the genome’
The success of exa-cel in clinical trials and the greenlighting by the FDA are profoundly important steps in the history of medical innovation.
“These approvals represent an important medical advance with the use of innovative cell-based gene therapies to target potentially devastating diseases and improve public health,” said Peter Marks, M.D., Ph.D., Director of the FDA’s Center for Biologics Evaluation and Research. “Today’s actions follow rigorous evaluations of the scientific and clinical data needed to support approval, reflecting the FDA’s commitment to facilitating development of safe and effective treatments for conditions with severe impacts on human health.”
Many believe we are at the dawn of a new age when it comes to treating disease.
“We are at the precipice, if not already over the precipice, of an entirely new era in humanity,” said Oakes. “You started out in the Stone Age, and then we moved on, and we got to the Iron Age, and now we’re in the Information Age,” he continued. “We’re no longer there. We are now in the age of the genome, in the age of CRISPR. When we look back 100 years or 1,000 years from now, are we going to remember anything else? Is there going to be anything else in the textbook other than in the early 2000s, humanity learned how to modify its own genome? I do not think that there will be anything as important as that. This is the future, period.”