Pankaja Arora, M.D., and Garima Arora, M.D., with members of the Cardiovascular Clinical and Translational Research ProgramThe University of Alabama at Birmingham has made history by dosing the first patient in the world in a first-in-human clinical trial of an investigational gene therapy for BAG3 mutation-associated dilated cardiomyopathy, a rare inherited form of heart muscle disease that can lead to progressive heart failure.
The Phase 1/2 clinical trial is an international study, with 11 participating sites worldwide, sponsored by the global biopharmaceutical company, Alexion, AstraZeneca Rare Disease. The study is evaluating an investigational one-time intravenous gene therapy for adults with dilated cardiomyopathy caused by a disease-causing mutation in the BAG3gene. Pankaj Arora, M.D., professor in the UAB Division of Cardiovascular Disease and director of the Cardiogenomics Clinic, serves as principal investigator for the UAB site. Garima Arora, M.D., director of Cardiovascular Imaging, and Mustafa Ahmed, M.D., director of the Structural Heart Program and Valve Clinic, serve as co-investigators.
Dilated cardiomyopathy occurs when the heart’s main pumping chamber becomes enlarged and weakened. As the heart muscle loses strength, it becomes harder for the heart to pump blood to the rest of the body. Patients may develop shortness of breath, fatigue, swelling, abnormal heart rhythms, and the need for implanted defibrillators, advanced heart failure therapies or heart transplantation.
In some patients, DCM is caused by inherited changes in genes that are important for normal heart muscle function. One of these genes is BAG3. The BAG3 gene helps heart muscle cells maintain normal structure and function by supporting the cell’s ability to manage stress and remove damaged proteins. When the BAG3 gene does not work properly, heart muscle cells may become more vulnerable to injury, which can contribute to weakening of the heart over time.
Current treatment for BAG3-associated DCM includes guideline-directed heart failure medications, rhythm monitoring, implantable devices when needed and advanced heart failure care. These therapies can improve symptoms and outcomes, but they do not directly replace or correct the abnormal BAG3 gene function that contributes to the disease.
Mustafa Ahmed, M.D. The investigational gene therapy is designed to deliver a working BAG3 gene to heart cells. The investigational therapy is given as a single IV infusion. The goal is for heart cells to begin producing functional BAG3 protein, potentially addressing one of the underlying biological causes of the disease.
“This is a historic moment for patients with inherited cardiomyopathy and for the field of cardiovascular gene therapy,” Pankaj Arora said. “For many years, we have treated heart failure by managing its consequences. This study represents an effort to move closer to the root cause of disease by targeting the genetic abnormality that contributes to heart muscle dysfunction.”
The study is designed to evaluate the safety, tolerability, and early biological and clinical effects of this investigational gene therapy in adults with BAG3 mutation-associated DCM. Because this is an early-phase, first-in-human study, participants are closely monitored before, during and after dosing.
“This trial brings together cardiogenomics, advanced heart failure care, cardiac imaging, interventional cardiology and translational research,” Garima Arora said. “For families affected by inherited cardiomyopathy, genetic diagnosis is an important first step. The long-term goal is to develop therapies that are guided by the specific genetic cause of disease.”
The first patient was dosed at UAB by a multidisciplinary team that included cardiologists, interventional cardiology, neurologists, hematology-oncology, imaging experts, inpatient nursing teams, pharmacy, regulatory personnel and clinical research staff.
“In a study like this, procedural safety and coordination are essential. This milestone reflects careful planning and close collaboration between the interventional, clinical and research teams,” Ahmed said.
Nehal Vekariya, who oversees the Cardiovascular Clinical and Translational Research Program at UAB, and Ishita Patel, the study coordinator, led the startup activities and coordinated the operational preparation required to activate and conduct the study at UAB.
More information about the clinical trial is available at ClinicalTrials.gov under identifier NCT07218887. To learn more about cardiogenomics research and cardiovascular care, visit the UAB Cardiovascular Institute.
“A first-in-human cardiovascular gene therapy trial requires detailed coordination across many areas, including regulatory approvals, protocol training, pharmacy preparation, inpatient logistics, research procedures, safety monitoring and communication with the sponsor,” Vekariya said. “This milestone reflects the strength of UAB’s clinical research infrastructure and the dedication of the entire study team.”
“Every step had to be carefully planned before the first patient could be dosed,” Patel said. “Our role was to make sure the protocol requirements were translated into a safe and organized clinical workflow for the patient, the investigators and all teams involved in the study.”
UAB has continued to expand its program in cardiogenomics and inherited cardiovascular diseases, integrating genetic testing, family-based risk assessment, advanced imaging, heart failure management and access to clinical trials. This study builds on that foundation and highlights UAB’s role in advancing precision medicine for patients with rare genetic heart diseases.
“The story is about one investigational therapy alongside the possibility of changing how we think about inherited heart disease,” Pankaj Arora said. “We are grateful to the patient, the family and every member of the UAB team who helped make this historic milestone possible.”
The trial is evaluating an investigational gene therapy, meaning it has not been approved by the United States Food and Drug Administration. Safety and efficacy have not yet been established. Participation in the clinical trial is limited to adults who meet specific study eligibility criteria.