Breaking the Chains: How CRISPR Gene Therapy Gave Victoria Gray a New Life
“I really gave up on becoming anything else. I thought sickle cell was just going to be my life from beginning to end.” – Victoria Gray.
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Like many young girls in elementary school, Victoria Gray wanted to be a cheerleader, until she was told by her doctor that this simply wouldn’t be possible; the exertion placed on her body by the training regimen could have devastating consequences. “That was my first disappointment as a kid,” she recalls.
Sadly, it wouldn’t be her last.
Tall for her age, Victoria later thought about trying out for a spot on the school basketball team. Her uncle had a great love for the game, which inspired her. Plus, everyone around her said she would probably have a natural knack for shooting hoops. Why not give it a go? She thought. But once again, her enthusiasm was shot down by another firm “no” from her pediatrician.
“My life was constantly full of ‘noes’, and people telling me ‘you can’t do this’ – it was limitation after limitation,” she says. “I had to alter everything I dreamed about, every step of the way from childhood to adulthood.”
If you’re lucky enough to grow up having a healthy childhood, it’s hard to imagine the cruel realities of experiencing a sick one. Victoria describes the motions of her life as though it was a distressing movie being played out in front of her, and someone – somewhere – kept hitting the pause button. Her days were shaped not by the whimsical imagination of a young child, but by her illness. That’s because at just three months of age she had been diagnosed with sickle cell disease (SCD).
SCD is a group of inherited blood disorders that cause red blood cells to become hard and sticky. In healthy individuals, red blood cells are a disc shape, allowing them to flow easily through our blood vessels. In SCD, they form a “C” shape known as a sickle, which causes the blood cells to die quickly or cause blockages in blood vessels. According to the National Institutes of Health, over 20 million people worldwide are affected by SCD.
SCD stole Victoria’s childhood, including her right to an education. “I had to alter everything I dreamed about every step of the way from childhood to adulthood. When I started college, I wanted to be a cardiologist. But doctors explained that the stress involved with studying medicine wouldn’t be good for me. So, I put myself on pause – once again,” she says.
Undeterred and eager to help care for others, Victoria started to explore a nursing degree, until “I had one the worst pain crises of my life,” she says.
Crises refer to acute conditions, such as the blockage of a blood vessel by sickled cells, caused by SCD. They are the main clinical hallmark of the disease, causing severe, debilitating pain and extreme fatigue, among other symptoms. Oftentimes, they strike at random, and can persist for long periods of time requiring extended stays in hospital.
“That crisis put me in the hospital for three months. I lost the ability to use my arms and my legs,” Victoria describes. Perhaps most devastatingly, she says, “I also lost my ability to dream.”
“I really gave up on becoming anything else. I thought sickle cell was just going to be my life from beginning to end.”
After undergoing comprehensive rehabilitation, Victoria eventually regained her strength and her ability to walk. But despite the physical improvements, mentally, she had to resign herself to the fact that a career maybe wasn’t on the cards for her. It was yet another blow, but one that she handled with the grace and determination she carried from a young age to find fulfillment in life. Victoria chose to focus her time, and the energy she could muster between crises, on being a wonderful mom to her four children, and a strong partner to her husband, Earl.
Then, in 2018, an opportunity came around that finally awarded Victoria the opportunity to say “yes” for the first time in her life. It was, she would come to learn, an opportunity that marked not only a major milestone in the history of medicine, but one that freed her from the chains of SCD – most likely, forever.
Finally, a “yes” for Victoria
Patients with SCD are often prescribed drugs, such as painkillers, to try and curb the symptoms associated with crises. These medications fail to target or cure the underlying cause of the disease, and while they offer symptomatic relief, they can have harmful side effects.
There are few authorized therapeutics on the market for SCD patients. In 2018, Victoria, who lives in Forest, Mississippi, was under the care of Dr. Haydar Frangoul, waiting to learn of her eligibility for one such treatment – a haploidentical “haplo” stem cell transplant using cells donated from her brother.
Dr. Frangroul is the director of the Pediatric Stem Cell Transplant program at Tristar Centennial Children’s Hospital, and an investigator at the Sarah Cannon Research Institute in Nashville. While at his clinic in Nashville, Victoria experienced a crisis that would ultimately change her life. “I had to be admitted, and during that hospital stay Dr. Frangoul approached me at my bedside. He knew that I was feeling really down, and he offered me a second option besides the Haplo transplant,” she recalls.
Victoria had some reservations about the Haplo transplant, largely due to the risk of graft versus host disease, a complication that can occur when a donor’s cells attack the recipient’s: “Dr. Frangoul told me that they were starting a new trial soon using CRISPR gene therapy. I hadn’t heard about it, so he showed me a small video on his phone and sent me a link so I could review it later.”
“Dr. Frangoul explained CRISPR therapy to me like this: he said, ‘just imagine a textbook with thousands and thousands of words, and there are a few words in there that are incorrect. The CRISPR technology could go into the cells, find the incorrect word and edit it without changing the story’.”
As with any clinical trial, there were risks involved. Given that Victoria would be the first patient to ever receive this experimental therapy, these risks felt somewhat heightened. She had a difficult decision to make.
“I'm a woman of faith – I pray a lot. I went to God, in private, about graft versus host disease, because I really didn’t want to experience that. So, when gene therapy came along, I felt like it was my answer from God, as though he was saying to me ‘I remove your fears now. This opportunity is for you’,” Victoria says.
Ultimately, the possibility of a life that would not be plagued by pain outweighed any doubts she might have had about being patient one. Within 24 hours of speaking to Dr. Frangoul, Victoria took the courageous decision to volunteer for the trial.
In July 2019, she became the first patient to receive CRISPR gene therapy for SCD.
“The trial was a different experience to anything I’ve had before, because for the first time, I felt hopeful. I was fighting for my life, and for my family.” Sure, I had to travel back to Nashville a lot for testing, and there were times [during the trial], especially after the chemotherapy, that it was hard. But my dad was with me, and he kept reminding me, ‘Vicky, you’ve seen worse, you are strong enough to get through this’. It helped to lift me back up and remind me of why I was doing this.
Victoria in hospital during her treatment. Credit: Victoria Gray.
Am I dead?
Eight months after the therapy was administered, Victoria woke one morning and felt “different”, though she couldn’t quite place what that meant. “I remember waking up, and the room was really bright. I didn’t feel anything, which was strange. I didn’t have any shortness of breath when I stood up, as had been the case most mornings,” she says.
Having lived most of her life in excruciating pain and extreme fatigue, the experience of waking up in its absence was so downright bizarre, Victoria had convinced herself that she must be dead. Pinching the skin on her face, and her thighs, she was reassured to feel the sharp, physical sensations.
“I shouted to my kids, ‘Hey y’all, come in here!’, and as they entered the room, their faces lit up. I knew in that moment, they could see me, and I realized that I was very much alive. I cried tears of joy, because I knew then that the gene therapy had worked,” Victoria describes, visibly emotional.
That bright, beautiful morning was four years ago, and it marked Victoria’s new beginning.
She describes her life now as one of freedom. She is free from constant pain and exhaustion. Free from having to stare at a hospital room’s four walls while experiencing a crisis episode. Free from relying on medication just to make it through the day. Free from all the ways that SCD stole her autonomy and chained her to a life burdened by illness.
Victoria can now play with her children and embody the parent she always dreamed of being. She can immerse herself in typical mom activities, often taken for granted as mundane, but that were once out of her reach. She can make choices. She can travel abroad – even flying to London last year to speak at the Third International Summit on Human Genome Editing.
Victoria and her children celebrating Christmas. Credit: Victoria Gray.
Eventually, Victoria’s health improved to the extent that she could realize her ambition of working full-time, securing a position as a cashier at her local Walmart. It was during a particularly busy shift on December 8, 2023, when she received news that the US Food and Drug Administration (FDA) had decided to approve Casgevy for the treatment of SCD.
“When I saw the text [from my husband], that the FDA had approved Casgevy, I had to rush off the floor at Walmart because I felt the tears coming,” she says. “I got in my car, and I just cried. I was so, so happy because I knew what a relief this would be for other sickle cell patients that were in a dark place like I had once been. Now, there was hope.”
Casgevy’s approval was based on data submitted from the trial that Victoria herself had bravely participated in.
The trial’s primary outcome had been freedom from severe vaso-occlusive crises for at least 12 months during the study’s 24-month follow-up period. In total, 44 patients were dosed with Casgevy. Upon submitting the trial data, 31 patients had sufficient follow-up time to be evaluated. Of these, 29 patients reached the primary efficacy outcome, with 0 patients suffering from graft failure or graft rejection – the trial had proven a success. Casgevy became the first gene therapy utilizing CRISPR-Cas9 to receive FDA approval, marking a historic moment for the SCD community, as lovotibeglogene autotemcel (LyfgeniaTM) – another cell-based gene therapy for SCD, developed by Bluebird Bio Inc. – also received a green light from the agency.
SCD patients face medical and racial discrimination, hindering clinical research prospects
Victoria received many phone calls that day, including one from a nurse who treated her at Dr. Frangoul’s clinic in Nashville. “We both cried,” she says, “It was tears of pure joy, because all of the pain, disappointment and judgement that I had faced from childhood now felt worth it. This was going to bring about change for other people who feel alone and feel overlooked.”
“It had felt as though nobody was coming to save us. Then suddenly we had a novel therapy for the SCD community. I felt so happy and grateful,” she adds.
While reminiscing, Victoria takes a moment to pause. It’s clear that the emotions attached to these memories are a complex mixture of elation and pain. “I want to emphasize that, had it not been for the positive way in which I was treated by Dr. Frangoul and his team, I might not have accepted the opportunity to take part in this trial that has saved my life,” she says.
Discrimination is an issue encountered by many SCD patients across the globe during their lifetime. In a perspective piece published in 2020, Power-Hays and McGann expressed that there may be “no population of patients whose health care and outcomes are more affected by racism than those with SCD.”
During the 1970s, many African American people were deprived of jobs, educational opportunities, marriage licenses and insurance in the US if they carried the SCD trait. This grim picture was mirrored across the pond in the UK. “In the 20th century, I'd say that racism showed itself in the lack of willingness on the part of statutory services, such as education, social services and housing, to take account of the needs of those living with SCD,” says Professor Simon Dyson, director of the Unit for the Social Study of Thalassaemia and Sickle Cell at De Montfort University in the UK. “In terms of sickle-cell screening, SCD had to meet prevalence thresholds not demanded of other rarer conditions, before newborn screening to save the lives of black infants was eventually made universal in England in 2004.”
A 2018 systematic review by Dr. Dominique Bulgin and colleagues explored the extent of health-related stigma in adolescents and adults living with SCD, analyzing data from 27 studies published between 2004–2017. They found that people with SCD experience health-related stigma based not only on their race, but on their disease status, socioeconomic status, delayed growth and puberty and having chronic and acute pain, requiring opioid treatment.
“Individuals with SCD reported being stigmatized as drug seeking or drug addicts and having their experiences of pain discredited by healthcare providers,” the review states. Sadly, this experience is one that resonates with Victoria.
“I was once in the emergency room when a nurse said to me, ‘You know, I feel so sorry for you sicklers’ – this was a term he used – ‘because you guys just get addicted to these pain meds, and then you can’t tell the difference between withdrawal and a real crisis’,” she says.
“He then said that it’s just inevitable that all SCD patients become drug addicts. I couldn’t believe it. I was in crisis. I was in pain, and I was crying out to a person who was supposed to help me. Instead, he judged me,” she continues. This, sadly, was not an isolated incident.
Victoria recounts another crisis episode, where she felt as though her symptoms of pain were starting to improve. She asked the nurse treating her to avoid administering any excessive pain medication that might make her feel drowsy, as she wanted to sit up and try to move around the room. Instead, the nurse pressed the button on her medication dispenser, and Victoria fell asleep. When she woke, she learned that instead of pain medication, the nurse had given her a different type of drug because they “wanted to see what it would do”.
Unfortunately, there was little consequence for the nurse, but the ramifications for Victoria were heartbreaking, she explains, and led her to question her worth as a SCD patient: “I felt as though the nurse had been given the right to experiment on me without my consent. What if that drug had taken my life? I couldn’t trust the staff that was treating me, I felt as though I was a burden, like they were trying to get rid of me when I was coming to them for help.”
“There is no way,” Victoria adds, “that I would have accepted an experimental treatment like gene therapy, if I had been offered it at this facility.” Research shows that she is not alone in feeling this way.
In 2020, Cho et al. conducted a study examining the motivations and decision-making processes of enrollees and decliners of high-risk trials for SCD. Of the 26 SCD patients interviewed, the majority reported negative interactions with health care providers. These experiences were so bad that many individuals had chosen to avoid hospitals during significant pain crises.
If SCD patients are afraid to even ask for help when they are in pain, how can they be expected to partake in high-risk clinical research? It’s an almost impossible decision, but it’s one that Victoria chose to make for herself, for her family and for the SCD community. It’s a decision that, now, in hindsight, she is thrilled about, but she remains eager to warn the medical community of the risks they pose to the health of SCD patients – and the future of SCD research – by forgetting that the patient in front of them is a human being.
“Please, just treat us how you want to be treated,” Victoria asks. “We did not choose to have SCD. We did not choose the amount of medication we require to ease our pain. We just want to be cared for, and we want to feel normal. Please, treat use with respect.”
Patient advocacy and increasing access to gene therapies
Now, five years after the trial commenced, Victoria is undertaking her follow-up appointments – which last 15 years from the study enrollment date – as per the study protocol. These appointments monitor her health and assess the long-term efficacy and safety of Casgevy. As gene therapies are emerging drugs, whether or not they are effective for the duration of a patient’s life is yet to be determined. “I pray that it is a forever change, and I believe that it is,” Victoria says.
She is enjoying applying her newfound energy to spread the word about her experience as an SCD patient, and a CRISPR gene therapy recipient, through advocacy work.
Once the news broke that she was the first patient to receive CRISPR gene therapy for SCD, Victoria was invited to speak with SCD organizations, meet other patients – or “warriors”, as she refers to them – and attend international events to share her story. “When I was flown to London to speak at the summit on human genome editing, I was amazed, because people really cared about my experience,” she says.
A recent highlight, she says, was her appearance on Good Morning America, where Victoria was able to meet a fellow SCD patient – Jamie – who had been inspired by her story and made the decision to receive CRISPR gene therapy. “It was truly a fulfilling moment,” she recalls, “because it was one thing that I hoped for – to be able to affect someone else's life in a positive way. To see [Jamie] looking so healthy after not being able to leave the house, or struggling to take care of his children, it was just incredible.”
Victoria also had the opportunity to visit the production facility that created her CRISPR gene therapy. “I was like a kid, looking at the machines and listening to how everything works. I know that this [therapy] was many years in the making, and it was an honor to meet the scientists that were working so hard when I thought no one cared.”
Her advocacy work has most recently turned to the costs associated with CRISPR-based, and other gene therapies, for SCD. A major challenge for patients and clinicians in accessing such emerging therapies will undoubtedly be their price. While information on the exact cost is currently limited, Casgevy will reportedly be priced at $2.2 million per patient in the US, and over £1.5 million per patient in the UK. Granted, it’s designed to be a “one-and-done” treatment, which could override economic burden of a lifetime of prescriptions, hospital stays and other associated costs with SCD management. But very few people – especially marginalized patients – have $2.2 million at their disposal, and in the US particularly, there’s lingering uncertainty as to whether most insurance companies will cover the therapies.
“When I heard the price after the approval, it made the moment bittersweet,” Victoria says. “I knew that, for me, if I would have had to pay for it, I wouldn't have been able to afford it. Because I couldn't even work. Speaking to SCD patients through my work, it’s clear that other patients and their families feel the same way.”
There is major research work going on across the globe in an attempt to reduce the costs associated with gene therapies, including those that are CRISPR-based. One example is a proposed movement towards in vivo delivery of gene therapies, which could reduce the costs associated with extracting cells, editing them in a laboratory and then infusing them back into the patient. At present, this research is in the laboratory stage, rather than clinical testing.
The Innovative Genomics Institute (IGI) is a non-profit academic institution that was founded by Professor Jennifer Doudna, who became a Nobel Laureate in 2020 in recognition of her research discovering CRISPR gene editing technology. It’s a joint effort between leading research institutes in the Bay Area, including the University of California (UC) Berkeley and UC San Francisco, with affiliates at UC Davis, Lawrence Berkeley National Laboratory, Lawrence Livermore National Laboratory, Gladstone Institutes and and other institutions.
Dr. Melinda Kliegman, director of the Public Impact at the IGI, recently led the IGI’s Affordability Task Force in generating a report, titled “Making Genetic Therapies Affordable and Accessible”. The task force assembled in 2021 to start work on the report, which explores the key drivers of the high prices associated with gene therapies and identifies approaches to increase their accessibility.
“The IGI develops the underlying technology used to make these [gene] therapies, but we are not involved in commercialization and pricing. We wanted to understand more about what goes into setting these prices, and what, if anything, we could do to lower them,” says Kliegman.
“The process of assembling the task force and developing the report took over a year and involved 35 task force members. The breadth of expertise of task force members helped us cover the many different complex issues that lead to high prices of gene therapies. It was a huge effort, but interesting, since we were all learning new things,” Kliegman adds.
The report is 75 pages long and provides a comprehensive overview of the various factors contributing to the current pricing of gene therapy. Kliegman summarizes the key “take home points” of the task force’s findings: “The issues affecting affordability are multifaceted and system wide. I would like to acknowledge that these therapies are expensive and difficult to manufacture, and there are small patient populations from which to recover costs,” she says.
“Companies also need to make a profit and adequate returns for investors. Given this, a for-profit company may not be the best business model for developing bespoke gene therapies. We need a paradigm shift in the way these therapies are commercialized, for example utilizing non-profit medical research organizations and public benefit corporations running on moderate-cost capital from social impact investors and government and philanthropic grants,” Kliegman continues.
As part of the report, the IGI team built a model that shows it could be possible to commercialize a gene therapy for 10x less than they are currently marketed at today, roughly ~$250,000 per patient for a therapy that could treat 2000 patients per year. This model is a departure away from the traditional methods used to develop gene therapies, and so, responses to the report have been mixed, Kliegman says. “Our proposal is oriented towards access, not profit maximization. Many people think it's naive to expect anyone to ‘leave money on the table’, while others agree with the need to improve access and affordability.”
There is change on the horizon, though: “We have had the privilege of meeting with organizations aligned with the suggestions in the report. Unsurprisingly, some of them had representatives on our task force,” Kliegman emphasizes. “The 90-10 Institute recently launched, which is a nonprofit working to establish an impact investment fund for public benefit pharmaceutical companies. There are also organizations like Odylia Therapeutics and Caring Cross, which are nonprofits developing and delivering gene therapies and public benefit manufacturing organizations like Landmark Bio and Vector BioMed.”
In Victoria’s mind, the high price of gene therapy is “just another hurdle to overcome”. She remains optimistic that the industry will reach a collective decision on how to ensure all patients can access the therapies they so desperately need. One day, she hopes that there will be no SCD patients having to attend emergency rooms, receive transfusions or rely on pain medication.
“I can live with the title of being a sickle cell warrior – I think we all can. But I want everyone in this community to be free from the hold that the disease places on our lives.” That is her dream, she says, and unlike the dreams that SCD denied her in childhood, hopefully, science can make this one come true.
About the interviewees:
Victoria Gray was the first sickle cell anemia patient in the world to be treated with CRISPR gene editing in 2019. After a lifetime of pain, treatments and hospitalizations for sickle cell disease, she is now symptom-free and working as a patient advocate and international speaker to spread the word about CRISPR and rare disease to clinicians, scientists, patients and students.
Melinda Kliegman is director of public impact at the Innovative Genomics Institute (IGI). In this role, she leads the Public Impact team, which works to align IGI’s genome-engineering innovations with societal values by engaging in public dialogue, original research, and policy creation through outreach to key stakeholders to ensure that genome-editing technology benefits everyone equitably. Melinda holds a PhD in Biology from Stanford University. Before joining the IGI, she worked at the Bill & Melinda Gates Foundation, the world’s largest philanthropic organization.
