Optimizing language for effective communication of gene therapy concepts with hemophilia patients: a qualitative study

Background For communities of people living with hemophilia and other genetic conditions, gene therapy could represent a paradigm shift in treatment strategies. As investigational therapeutic modalities such as gene therapy become more widely used and discussed, there is a critical need for all stakeholders to communicate using a lexicon that is intelligible, accurate, consistent, and representative of novel treatments. In doing so, expectations can be more carefully managed and potential risks, benefits, and limitations better understood. In recognition of this need, a first-ever study of gene therapy lexicon was conducted using established methods of market research and linguistic analysis. Methods Ninety-four participants representing hematologists, nurses, caregivers, and people with hemophilia A, in six countries (US, UK, Spain, Germany, France, Italy) took part in a series of in-depth interviews, face-to-face focus groups, an advisory board meeting, and online group interviews to develop, refine, and test verbal, written, and pictorial language concepts through a three-phase iterative process. Sessions were conducted in local languages using detailed discussion guides. Feedback from participants was captured using real-time instant-response dial testing to measure moment-by-moment emotional responses to language stimuli. Semiquantitative analysis of the responses informed selection of preferred language concepts for final testing, and qualitative discussion explored preference rationale. Participants also completed polling and forced rank and choice written exercises. Results Study feedback showed that the hemophilia community has preferences around consistent lexicon to describe hemophilia and its management. Expert linguistic analysis of feedback from the three phases enabled agreement of a consensus lexicon of vocabulary and an optimized summary narrative for talking about gene therapy amongst people affected by hemophilia A. Preferences were largely consistent across audiences and countries, although some country-specific recommendations were made. A representative summary phrase was agreed: “Gene therapy is being studied in clinical trials with the aim to allow the body to produce factor VIII protein on its own”. Conclusions The use of preferred language across different stakeholders increases understanding and comfort during discussions of novel and complex therapeutic modalities such as gene therapy. Consistent use of community-informed lexicon minimizes miscommunication and facilitates informed decision-making regarding potential future treatment opportunities.


Story Flow Option B -The Middle Ground Approach
What is gene therapy? → Mechanism of disease/ Why hemophilia A? → How does gene therapy work? → Goals of gene therapy • Gene therapy is a novel treatment approach in which genetic material is used to treat the biological basics of hemophilia A. • The method of gene therapy that is currently in clinical trials for hemophilia A is called Adeno-Associated Virus (AAV) gene therapy. Because of a genetic variance, people with hemophilia A don't produce enough of the Factor VIII protein, which is necessary to form stable clots in their blood. AAV gene therapy targets the gene responsible for creating Factor VIII. • In AAV gene therapy, a functional gene is inserted into a nonpathogenic virus which acts as an envelope to deliver the new gene into the body via a single IV infusion. There is no replacement or editing done at a genetic level -just the introduction of a new, functional factor VIII gene into the body, which is not passed down to future generations. • The goal of this treatment is to provide patients with the ability to produce and maintain a higher baseline level of factor VIII.

THEME STORY FLOW OPTIONS FOR DISCUSSION (PHASE III)
Story Flow Option C -Leading with Goals

Goals of gene therapy → What is a gene? → Mechanism of disease → What is gene therapy? → How does gene therapy work?
• Empowering you and your loved ones to live life without the constant weight hemophilia A puts on your shoulders is what gene therapy is all about. • In your body, genes are pieces of DNA, which provide the step-by-step instructions for making proteins like factor VIII. Hemophilia A patients inherit or spontaneously develop a genetic mutation that inhibits their bodies' ability to make factor VIII -the protein that allows blood to clot. • Gene therapy is a revolutionary treatment approach for patients like you, and is currently undergoing clinical trials. In this approach, a working gene is inserted into a neutralized viral shell, which is then delivered into your body via a one-time IV infusion. No genes are removed or replaced in this process -the new gene is simply added to do the extra work the original gene that causes the genetic disorder (disease) could not do. • The goal is that the new gene provides the genetic information necessary to produce factor VIII at a level you need to live your life free from the emotional and physical burden that comes with having hemophilia A.

Mechanism of disease → What is gene therapy? → How does gene therapy work? → Goals of gene therapy
• In a person without hemophilia A, genes in the liver and other parts of the body provide the instructions needed to produce Factor VIII, a protein needed for clotting. But in a person with hemophilia A, a genetic mutation makes it so that not enough Factor VIII is produced. • That's where gene therapy comes in. Gene therapy is a new kind of treatment for hemophilia A.
Unlike traditional factor replacement therapy, it doesn't just replace the missing factor. It works to restore cellular function, allowing them to produce Factor VIII. • The type of gene therapy that may soon be available for hemophilia A patients is called gene transfer. In gene transfer, a new, functional gene is inserted into a protein shell, which is then administered to the patient in a single IV infusion. This protective shell, which is made from a neutralized virus, carries the functional genetic material into the liver. In the liver, the new gene goes to work to replace the function of the mutated gene. • Ultimately, this process allows the liver to produce Factor VIII itself. That means the potential for no more prophylactic or on-demand factor replacement, and a life post-hemophilia.

Story Flow Option E -Original Flow
What is a gene? → Mechanism of disease → What is gene therapy? → How does gene therapy work? → Goals of gene therapy • A gene is the blueprint for constructing your body's unique individual traits such as bones, teeth, muscles, skin, hair and blood, as well as proteins that help your body function, such as factor VIII. • A variation in a gene can be harmless. However, some changes in a gene's DNA sequence can cause genetic conditions like hemophilia A. Hemophilia A is caused by a mutation in the factor VIII gene, which impedes production of this key clotting factor in the blood. • For many years, the primary way to manage hemophilia A has been through factor VIII replacement therapy -either prophylactic, on-demand, or both. Replacement therapy helps manage and prevent symptoms. But for many patients there is still an unmet need. • Unlike traditional replacement therapies, gene transfer targets the root cause of hemophilia A.
A new, functional gene is inserted into a vehicle made from a non-illness causing virus, which is delivered into the patient via a single IV infusion. • While still undergoing clinical trials, gene transfer has the potential to allow severe hemophilia A patients with the ability to produce their own factor VIII -something they have never been able to do before.