Are these the most dangerous four-letter words in sickle cell treatment?

Everyone has a favorite four-letter word—often one that captures frustration, fear, or something deeply felt. For Dr. Yoram Unguru, a pediatric hematologist/oncologist and bioethicist at The Children’s Hospital at Sinai and Johns Hopkins Berman Institute of Bioethics, three four-letter words carry particular weight: hope, hype, and cure.

In the evolving landscape of gene therapy for sickle cell disease, these words aren’t just expressions—they shape expectations, influence decisions, and define how patients, families, and clinicians navigate a rapidly changing treatment frontier. As breakthroughs move closer to reality, the challenge is more than scientific.

It requires understanding what these words truly mean and what they promise.

I recently sat down with Unguru to explore how these ideas are shaping the conversation, and what they reveal about the promise and complexity of gene therapy today.

Your keynote explores three powerful “four-letter words”: hope, hype, and cure. Why are these concepts so important in the context of gene therapy for sickle cell disease, and how have they evolved over the past decade as these therapies have moved closer to clinical reality?

The first thing we need to acknowledge is that, biologically, the type of genetic mutation that causes sickle cell—that single point mutation—means that sickle cell is an attractive disease for gene therapy.

Secondly, for decades, research into exploring and developing new treatments for sickle cell was overlooked while less common diseases like cystic fibrosis, hemophilia, and multiple sclerosis far outpaced sickle cell in funding, publications, and development of new medications.

Before gene therapy, the only potentially curative option for patients with sickle cell was a bone marrow transplant (BMT). To this day, BMT remains an option for a relatively small number of patients, mainly due to a lack of matched donors and the risk of complications associated with need for preparative chemotherapy regimens and, depending on the degree of match, potential graft versus host disease. It makes sense that people living with this chronic, debilitating, life-limiting disease—along with their families and the clinicians who treat them—be excited about the emergence of gene therapy. That excitement fueled hope, which in turn generated hype. Even though a relatively small number of people were involved in early trials, the results looked pretty encouraging, and it didn't take long until stories in the media began to extoll the promises of gene therapy. Hype was everywhere, and the word “cure” was pervasive.

For patients with sickle cell disease and their families, how do narratives around hope, hype, and cure influence decision-making?

Each of us, including people living with sickle cell, is influenced by our environment. What we see, what we're told, how we're told, the way information is framed—that all influences how and what people with sickle cell and their families think about gene therapy. Because of this, colleagues and I conducted a multicenter study engaging with focus groups consisting of patients living with sickle cell disease and their caregivers to better understand their perspectives and knowledge of high-risk, high-reward treatments like gene therapy. Fewer than 5% of respondents said they felt extremely knowledgeable about gene therapy, and about two-thirds said they had no knowledge of gene therapy. Not surprisingly, greater self-reported knowledge of gene therapy was associated with higher levels of comfort and confidence in safety and effectiveness. I asked myself: Why does being more knowledgeable about gene therapy translate to this greater willingness to accept it as a treatment? Is it because of hope? Hype? Or something else?

What we found through was that many respondents were much more skeptical about gene therapy than what was portrayed in the media. While many academic and other publications portray the sickle cell community as all-in for gene therapy, we found a very different perspective. In fact, most people we worked with said they were more worried about the side effects associated with gene therapy and only a small percentage felt that gene therapy might be right either for them or their child. We also found some patients who had undergone gene therapy regretted doing so. One of the study’s biggest takeaways was a clear message from patients and families: Don’t just sell the upside—be honest about the downside too.

Could you elaborate on those downsides you mentioned?

Currently, like bone marrow transplantation, gene therapy requires patients first undergo chemotherapy, which can be really hard on them. Think of the bone marrow as a garden. A healthy garden has trees, flowers, bushes, and grass, and everything looks great, but if your garden is not healthy, because of sickle cell, it gets “weeds.” To tidy the garden, you use chemicals like a weed killer, or you pull out the weeds by hand. In sickle cell, to prime the bone marrow to accept gene therapy, you give chemicals in the form of chemotherapy to eliminate the existing bone marrow. Then, after a patient’s cells have been re-engineered in a lab, those modified cells are infused back into their body. So, before a patient sees the potential upside of the gene therapy, they have undergone chemotherapy, which is indiscriminate and can cause side effects like infertility or organ damage. That is one of the major downsides with current approaches to gene therapy. Also, gene therapy isn’t like Marty McFly in Back to the Future—it can’t go back in time and reverse damage that's already happened. If a patient has experienced complications from sickle cell disease, like a stroke or bone necrosis, those conditions won’t be undone by the treatment.

Presently, there are trials in development that hopefully will minimize some of these downsides. These trials are exploring in vivo gene therapies, which eliminate the need to send cells to a lab for re-engineering or to use chemotherapy. If proven safe and effective, these gene therapies will be administered to the patient like many other medicines. It’s equally important to understand what matters most to patients and their caregivers—and to make sure those priorities are reflected in the design of these trials.

Beyond the science, what are the biggest real-world barriers to delivering on the promise of cell and gene therapy?

What's that old real estate adage—location, location, location? When it comes to sickle cell disease and gene therapy, location absolutely is at the forefront. The cost of these gene therapies range from $2-3 million per treatment, which means gene therapy is inaccessible to most of the world's patients with sickle cell disease because of where they live and the challenges they face from an economic and/or infrastructure perspective.

Even if we look at the U.S., one of the wealthiest countries in the world, there are countless challenges to realize gene therapy for sickle cell. About 100,000 people live with sickle cell disease in the U.S. Figuring out how we pay for gene therapy raises many policy considerations. From an infrastructure standpoint, relatively few centers can deliver these treatments and care for patients, with current estimates suggesting that only 25-30 centers nationwide are truly equipped to administer gene therapy and safely care for patients. The required technical expertise and complexity of these still-new therapies means that even highly experienced centers can only treat about 5-10 patients per year.

If we return to the issue of money, globally, there are about 8 million people who have sickle cell disease, the vast majority of whom live in Africa and India. In many of these countries, basic sickle cell care is a struggle, and in its current form, transformative treatments like gene therapy are untenable. Currently and on a meaningful scale, to deliver and support gene therapy in Africa, India and other international locations is impossible. Equity and access are a real barrier to gene therapy. It’s great we have such promising treatment, but when it's out of reach for most patients, what does that mean?

Given all these access, geopolitical, financial, and economic issues, how do you see the future of these therapies evolving over the next few years?

Because gene therapy is a scarce resource, we need systems in place to ensure its fair distribution and allocation. In the U.S., an interesting and important effort, led by the Centers for Medicare & Medicaid Services (CMS) Innovation Center, is a good model. CMS has instituted an outcomes-based gene therapy model with the goal to broaden access to expensive treatments—with gene therapy for sickle cell disease serving as the test case. Under the model, CMS and manufacturers negotiate discounts and outcomes-based rebates from which form the basis for individual contracts between the manufacturer and participating states. Currently, Medicaid programs in 32 states, Puerto Rico, and the District of Columbia have voluntarily signed on with CMS.

Also, the expectation is with time, prices will come down, but at $2-3 million per single treatment, the cost will need to decrease significantly to allow for patients to benefit.

What advice would you offer to health system leaders as they prepare to integrate cell and gene therapies into care delivery?

First, just because you can doesn't mean you should. There are a lot of centers that may view gene therapy as a “golden goose” and rush to launch programs. I mentioned that, globally, too many patients with sickle cell disease don’t receive the basic standard of treatments and care. To a lesser degree, the same holds true here in the U.S. where basic and effective treatments like hydroxyurea and timely screening studies like transcranial Doppler are underutilized. Before we roll out gene therapy, it stands to reason that we do a better job assuring that standard of care treatments and approaches are widely adopted. Not every patient with sickle cell needs gene therapy; some will do just fine with standard treatment modalities.

Although we absolutely do need more centers that can safely and effectively deliver gene therapies, we need to be transparent about what gene therapy can and can't do. The word “cure” is thrown around too cavalierly. What “cure” means likely varies from individual to individual such that my definition of cure may not be your definition of cure, which may not be our patient's definition of cure. For example, for clinicians, a gene therapy “cure” may mean eliminating sickle hemoglobin and the absence of graft versus host disease or no longer needing disease-directed treatment while for patients and families, “cure” may mean being pain-free and regaining lost organ function. But, as I mentioned earlier, if organ damage has already occurred—such as from a prior stroke—gene therapy cannot reverse it. Making sure that patients and caregivers fully appreciate the limits of gene therapy, especially as relates to “cure,” is really important.

If you could change how one group—clinicians, media, industry, advocacy organizations, or policymakers—talks about gene therapy, who would it be and why?

I don’t think I would pick any one group. We all need to work together. How we communicate—as clinicians, investigators, regulators, media, and advocacy groups—has real influence. I would like for all of us to appreciate what it means when we use words like “cure” and be mindful of what people hear and how they interpret these words.

Looking ahead, what gives you the most genuine hope—and the most pause—for the future of gene therapy in the treatment of sickle cell disease?

I'm hopeful that the current momentum and interest in sickle cell disease will have legs and that as the field advances with improved and less toxic cellular and gene therapies, sickle cell will no longer be overlooked or left behind. My hope is that the promise of gene therapy serves as a catalyst for ongoing research and investment in sickle cell disease.

What gives me pause is much of what I’ve already mentioned. I worry that technology often advances faster than our ability to thoughtfully implement it. If the past 50 or 60 years of caring for people with sickle cell disease, including more recent experience, has taught us anything, it’s that we must be mindful about how these and other therapies are studied and delivered. We absolutely owe it to patients with sickle cell to ensure that treatments are safe and are broadly available in a way that doesn't break the bank. That, to me, is the heavy lift.