During his first year at BioMarin, Marius Sumandea recalls peers in his network often being surprised he decided to join a company early in its journey working to address cardiovascular disease.

“Then I tell them what attracted me is the possibility of really addressing the underlying causes of disease,” says Marius, who joined the company to lead its cardiovascular research unit in 2022. “I’ve spent most of my career thinking about solving problems of the heart muscle, but this is the first time I’ve felt like we have the infrastructure and the tools to go after the root causes of some of those problems.”

Marius leads a team of researchers working to leverage the company’s expertise in translating genetic discoveries into potentially transformative medicines to address the root causes of certain forms of heart disease. Since 2019, the company has been studying multiple treatment modalities – including gene therapy, oligonucleotides and monoclonal antibodies – that could help address the significant unmet needs that still exist for people living with cardiovascular conditions.

“Our cardiovascular program is a great example of how teams at BioMarin are leveraging our deep genetic knowledge to increase understanding of the biology underlying disease,” says Kevin Eggan, chief scientific officer, senior vice president, Research and Early Development. “We’re excited about the opportunity to develop new and transformative treatment options for people with cardiovascular conditions, many of which have not seen significant advances to the standard of care in years.”

Evaluating Gene Therapy Approaches

For certain forms of heart disease, the underlying cause stems from a genetic mutation that leads to deficiencies in specific proteins that play important roles in the function of the heart muscle.

By addressing these mutations with gene therapy, the theory is that the body could begin producing sufficient levels of these proteins to help restore normal heart function and halt – or potentially even reverse – disease progression.

For example, BioMarin is studying ways to address hypertrophic cardiomyopathy (HCM), a chronic disease characterized by the thickening of the heart muscle. As the heart thickens, it struggles to fill with enough blood to keep up with the demand of the body. This is often attributed to a genetic mutation that leads to a deficiency in a protein that plays a critical role in the normal contraction of the heart muscle.

Those living with HCM – the leading cause of sudden cardiac death in young adults – can be limited in their ability to exercise and may experience symptoms such as fatigue, palpitations, chest pain and fainting.

“Unfortunately, there are still significant unmet needs for people living with HCM,” says Catherine Vitelli, the lead research scientist for BioMarin’s HCM program. “Developing a therapy that is designed to target the underlying genetic cause of HCM by delivering a functional copy of the gene to replace the one affected by mutations is the ultimate goal of our ongoing research.”

Arrhythmogenic cardiomyopathy (ACM) is another form of heart disease that could be a potential candidate for a gene therapy approach. ACM is an inherited condition characterized by an enlarged, weak heart and abnormal heart rhythms called arrythmias. It is caused by a genetic mutation that leads to a loss of a protein needed to maintain the desmosome, a zipper-like structure that binds cardiac cells together. Over time, cardiac cells detach from one another and die, leading to scarring and fat deposits.

Strenuous exercise can lead to early onset of the disease in seemingly healthy adolescents and young adults, particularly competitive athletes. People with ACM are often advised to avoid exercise and have very limited therapeutic options. Some require invasive procedures such as the implantation of a device that shocks the heart during arrythmia.

“The hope of our gene therapy research is to reassemble these desmosome structures to help stitch back together cardiac cells and see if that can strengthen the heart and restore normal heart rhythm,” says Gouri Yogalingam, the principal scientist for the company’s ACM program. “This could represent an entirely new approach for helping people with ACM.”

Using a Monoclonal Antibody to Correct the Heart’s Electrical System

In other forms of heart disease known as cardiac channelopathies, genetic mutations may lead to issues with the function of channels that regulate the heart’s electrical current to create a coordinated heartbeat.

Long QT syndrome is a cardiac channelopathy that causes the heart to take longer to electrically recharge itself for the next beat. This can lead to sudden loss of consciousness or cardiac arrest when the heart essentially spins electrically out of control.

Depending on how the gene that makes the ion channel mutates, it can either lead to a longer QT interval, or shorter QT interval (short QT syndrome).

“The fact that different mutations in the same gene can lead to either long QT or short QT syndrome indicates that targeting this gene gives us the opportunity see if we can fine-tune and restore the normal channel function,” says Mustafa Kamani, the lead scientist for the company’s long QT syndrome research. “In a way, nature has done the proof-of-concept experiment for us.”

Studies have also shown that some people with another type of heart disease naturally produce antibodies that target this same channel, and the QT interval in these individuals is shorter than in those who don’t have the antibodies.

“This provides the rationale for researching and developing a monoclonal antibody to treat long QT syndrome,” says Mustafa.

Looking to the Future

BioMarin is starting its cardiovascular program by targeting specific sub-types of heart disease. But Marius notes that the learnings the company is accumulating may have much broader potential.

“We believe that understanding the genetic components of these diseases and taking this precision-medicine approach may allow us to form bridges into other forms of heart disease and help more people,” says Marius. “I believe this approach could help us shape the future of cardiovascular medicine.”