What’s the Meaning of ‘Cure’ in Gene Therapy?

Gene therapy comes with the expectation that it will “cure” an expanding number of genetic disorders. If you’ve never wondered – and even if you have -- what that word actually means, four Dutch researchers have a surprise in store.

Lieke Baas, M.Sc., M.A.

Their analysis, published Aug. 22, 2024, in Medicine, Health Care and Philosophy, delves into how “cure” is understood in different medical fields. They distinguish multiple “interpretations,” depending on the setting and the affected group of people, with perhaps unexpected expectations among patients about what will result from treatment and even, in some cases, if a cure is desirable.

The authors conclude that the term “cure” should no longer be used in clinical settings. But in two other contexts — decisions about allocating resources for gene therapy treatments and funding research proposals — they argue that it is useful but needs to be carefully and modestly defined.

First author Lieke Baas, M.Sc., M.A. and a Ph.D. candidate in biomedical ethics at University Medical Center Utrecht, Utrecht University, in the Netherlands, and colleagues in bioethics, philosophy and hematology, write that “cure” is rarely defined, even though it is used frequently by doctors in interactions with patients as well as in headlines about gene therapy clinical trial results in scientific journals.

Three definitions

By examining how the concept of cure is used in several medical fields in which it is contested and therefore regularly discussed — oncology, psychiatry, care for people with a hepatitis C virus (HCV) infection and care for deaf people — they identified three definitions:

Cure as normalization of the body. Regenerative medicine, for example, promises to replace or regenerate human cells, tissues or organs, thereby restoring normal function. This interpretation often involves statistics, for example no return of cancer for at least five years after treatment. The notion of normalization of the body has been criticized by people with disabilities, who argue that it does not value their lives and bodies.

Cure as obtaining a normal life. In this interpretation, cure is understood to mean an end to illness and its effects, as well as restoration of a prior state of health and well-being. Cure is seen as an end point. For many people with HCV, for example, most of whom were infected with the virus through injection drug use or in prison, an important part of a normal life is overcoming stigma. The cure-as-end point formulation has been criticized because it overlooks the ongoing experiences, needs and suffering of people after completing treatment. In addition, ability the obtain a normal life also relates to laws, policies and social structures, such as access to insurance or government benefits, and cannot be achieved solely by biomedical cure.

Cure as a change in identify. This interpretation focuses on how both the experience of illness and the transition to health can become integrated into a person’s narrative identity. People with HCV hepatitis C again provide an example, as they value treatment outcomes other than a sustained virological response, such as positive change in identify and impact on social connections. For them, according to qualitative research cited in the paper, a cure would not mean a return to normality but a “reawakening” or “rebirth” – high expectations that are difficult to meet. But the pros and cons of identity change may be different for people with disabilities: some deaf people see deafness as part of who they are and the social group to which they belong, so the idea of a cure for deafness is undesirable.

Some fields have already moved away from the concept of a cure. Psychiatric care has been moving toward “recovery” or “healing” instead. Oncologists, unsure about the risk of relapse, use terms like “remission” or “no evidence of disease.” People with cancer histories many years ago adopted “cancer survivor” to avoid being called patients and also to draw attention to the care required after active treatment as well as the health effects and emotional toll of a cancer diagnosis on family, friends and caregivers.

Trying them out on hemophilia

For gene therapy, examine the use of the term cure through the case of hemophilia, for which therapies have been approved by the FDA, with more under development. Because hemophilia is a single-gene disorder with a wide therapeutic window, it has often been seen as an ideal model for validating general gene therapy principles. Unlike many other gene therapy targets, however, the congenital bleeding disorder already has several good treatment options that give people with the disease in resource-rich settings a life expectancy comparable to the general population. In those circumstances the decision about whether to undergo extremely expensive gene therapy for hemophilia is likely to become, wrote Baas and her co-authors, “a personal choice in the palette of treatment choices.” In the U.S, of course, there will also be the gantlet of insurance coverage and other factors influencing the decision.

The authors try out the three definitions for cure that they developed on hemophilia and found that all three work to a greater or lesser extent. The most stringent clinical definition is a complete end to bleeding five years after curative treatment, requiring no further treatment of any kind, not even for surgery or bleeding. But this “normalization of the body”-type definition does not include eliminating transmission of hemophilia to offspring or recognize ongoing complications such as joint damage from previous bleeding.

Simultaneously, cure is used to refer to “obtaining a normal life,” but previously lost education, career opportunities and financial consequences cannot be returned to normal. The notion of “cure as a change in identity” comes up in the cited qualitative literature. In accounts of people living with hemophilia who reject gene therapy because they don’t want to lose their identity as a person with hemophilia. (Other family members may have the disorder.)

So, should “cure” continue to be used when discussing gene therapy?

In clinical settings, Baas and her colleague say in their paper that “in interactions between people with hemophilia and health care providers, it might be desirable to refrain from using the term cure, and instead opt for merely using specific end points and effects on quality of life when discussing potential benefits of a treatment or trial.”

In the context of deciding how to allocate the enormous resources required for gene therapy, such as insurance reimbursements, the authors write, “it is important to be explicit about what is meant with a cure and in what ways a product with a potential to cure differs from other treatment options, to assess what added value a cure may bring.” Therapies with a potential cure may have a special value that justifies a high price. Conversely, if cure is defined as a change in identity, there may not be much value to gene therapy for, say, hemophilia, as it may be an undesirable outcome.

As for research funding decisions on gene therapy, with the notion of a cure used in trial protocols and research proposals for new gene therapies, the authors write that including cure as an outcome measure requires endpoints that are specific in both measure and time (e.g. five years). Besides this “normalization of body” interpretation, they note that “obtaining a normal life” or “change in identity” often are included as secondary quality-of-life end points but perhaps should be considered as primary endpoints.

Baas and her co-authors also note that research proposals “regularly have to boost expectations in order to attract funding.” As a result, they add, “the term cure can contribute to hype and high expectations surrounding gene therapy, which may increase further when cure is ill-defined or interpreted differently by various stakeholders. Therefore, although use of the term can be valuable in this setting, it is important to be hesitant when translating these promises to other settings.”