As gene editing moves from the laboratory into clinical practice, transforming lives, we explore its potential for people with Marfan syndrome. With the same tool now treating both sickle cell disease and thalassaemia, an exciting question emerges: what might this one day mean for connective tissue and inherited aortic disorders?

From Sickle Cell Disease to Thalassaemia: What Gene Editing Could Mean for Marfan Syndrome by Dr José Aragon-Martin

In my previous article for the Marfan Trust, we explored gene editing and its potential to transform the treatment of genetic conditions, including sickle cell disease. We also considered what these developments might eventually mean for people living with Marfan syndrome.

Now, a recent BBC report provides another striking example of this technology in action. Vian, a 16-year-old from Coventry, has undergone gene editing for beta thalassaemia, an inherited blood disorder that had left her dependent on regular blood transfusions. Following treatment, she is producing her own red blood cells and no longer needs those transfusions. Her experience illustrates how advances in genetic research can make a profound difference to an individual’s life.

What makes this particularly interesting is that the same gene-editing treatment, known as Casgevy, can be used to treat both beta thalassaemia and sickle cell disease. Although these conditions arise from different genetic defects, both affect haemoglobin, the protein responsible for carrying oxygen in red blood cells.

Using CRISPR-Cas9, scientists edit a regulatory region of the BCL11A gene in a patient’s own blood-forming stem cells. This enables the cells to produce higher levels of fetal haemoglobin, a form of haemoglobin normally found before birth. In beta thalassaemia, fetal haemoglobin can compensate for deficient adult haemoglobin production, while in sickle cell disease it reduces the harmful effects of sickle haemoglobin.

Importantly, this treatment does not directly correct the original genetic mutation. Instead, it modifies the regulation of haemoglobin production to overcome some of the consequences of the underlying genetic defect. Following chemotherapy to prepare the bone marrow, the edited stem cells are returned to the patient, where they can establish themselves and produce blood cells that contain increased levels of fetal haemoglobin.

The success of this approach illustrates an important principle: two distinct genetic disorders can sometimes be treated using the same therapeutic strategy by targeting a shared biological mechanism rather than correcting each underlying mutation individually.


What does this mean for Marfan syndrome?

Marfan syndrome is biologically different from sickle cell disease and beta thalassaemia. It is most commonly caused by pathogenic variants in FBN1, the gene encoding fibrillin-1, a protein essential for the structure and function of connective tissue. These variants can disrupt connective tissue and contribute to manifestations affecting the aorta, eyes, skeleton and other organs.

Casgevy is not a treatment for Marfan syndrome, and the approach used for these blood disorders cannot simply be transferred to connective tissue conditions. Nevertheless, these developments demonstrate how understanding the molecular mechanisms of a disease can reveal new ways to intervene and potentially change its clinical course.

The fact that the same gene-editing therapy can treat two distinct genetic disorders also raises an interesting question for Marfan syndrome and other hereditary thoracic aortic aneurysm and dissection (HTAAD) conditions. Could a better understanding of the different genes responsible for these disorders reveal shared molecular pathways that might eventually be targeted by common therapeutic approaches?

Although the genetic causes vary, some inherited conditions can converge on common biological processes. Identifying these shared mechanisms could open the door to treatments that benefit patients with different genetic diagnoses, rather than requiring a completely different treatment for every pathogenic variant.


How does this relate to our research at the Sonalee Lab?

At the Sonalee Lab, we take these advances in genetic research very seriously. We are investigating how a better understanding of the genetic mechanisms underlying inherited diseases can reveal new opportunities to intervene at the molecular level and, ultimately, substantially change their clinical course.

One of our research programmes focuses on identifying new genetic causes of hereditary thoracic aortic aneurysm and dissection (HTAAD). By identifying the genes involved in these conditions, we aim to improve our understanding of the molecular mechanisms responsible for the clinical features observed in people with Marfan syndrome, as well as in individuals carrying pathogenic variants in other HTAAD-associated genes.

Identifying these genetic causes is only the first step. Our longer-term objective is to understand how the resulting molecular disturbances affect connective tissue and aortic structure and function, ultimately contributing to the clinical manifestations of these conditions. This knowledge may help us identify new molecular pathways that could be targeted therapeutically and, in the future, inform the development of more precise and effective treatments.

The experience with sickle cell disease and beta thalassaemia is particularly relevant to this ambition. If two distinct genetic disorders can be treated by targeting a shared molecular mechanism, could similar principles eventually be applied to Marfan syndrome and other HTAAD conditions?

This is an important question for our research. Although the underlying biology is different, investigating the genes responsible for thoracic aortic aneurysm and dissection may reveal common disease mechanisms and potential therapeutic targets. Such discoveries could ultimately benefit not only people with Marfan syndrome but also patients with other inherited conditions that predispose them to aortic disease.

The breakthroughs in sickle cell disease and beta thalassaemia remind us why this work matters. Gene editing is not currently an established treatment for Marfan syndrome, and substantial scientific and technical challenges remain. However, these advances demonstrate what can be achieved when a detailed understanding of disease biology is translated into a targeted therapeutic strategy.

The discovery of a candidate gene

Our aim at the Sonalee Lab is to first identifying the genetic causes of disease towards understanding how those genetic changes produce disease—and, ultimately, how that knowledge might be translated into better treatments for patients.

This is why supporting and donating to research is so crucial. The Marfan Trust is the principal funder of the Sonalee Lab, and without its support, we would not have been able to identify LMOD1 as a candidate gene associated with familial thoracic aortic aneurysm and dissection (HTAAD). This discovery represents an important step towards understanding the genetic basis of aortic disease, and our PhD student, Jessica Esther Alvarez-Salgado, is now undertaking further investigation and curation of LMOD1 to help establish its clinical significance.

Research funding enables us to do what we do best: investigate unanswered scientific questions, uncover the genetic causes of disease and translate these discoveries into a better understanding of the conditions affecting our patients and their families.

Resolving unresolved cases

This work is particularly important for families affected by HTAAD who receive negative results from genetic testing for currently known HTAAD-associated genes. We are delighted to have recruited Jessica, a bright and inquisitive PhD student, who will take on the challenge of identifying the underlying molecular and genetic causes of disease in these families. By investigating these unresolved cases, we hope to discover new disease-associated genes, uncover previously unknown biological mechanisms and, ultimately, improve genetic diagnosis while opening new avenues for future research and treatment.

Your support can help make this research possible. Every contribution helps us pursue the unanswered questions that matter to patients and their families, bringing us closer to understanding the genetic causes of aortic disease and, ultimately, developing better ways to diagnose, manage and treat these conditions.