Technology Overview

Pulmonary arterial hypertension (PAH) is a devastating rare cardiopulmonary disease of the pre-capillary arterial system in the lungs. The underlying molecular mechanism is associated with senescence processes occurring in pulmonary artery smooth muscle cells. Progressive remodeling of the pulmonary circulation leads to dramatic increases in pulmonary vascular resistance (PVR) and elevated mean pulmonary artery pressure. In the extreme cases, PAH becomes quickly fatal as right ventricular volume loading can increase greater than 5 times normal, distorting the function of the left ventricle.

At present, all current PAH medicines fail to address the formation of plexi-form lesions primarily occurring in the pre-capillary arterial system a major problem of PAH. Instead current PAH medicine only address the symptoms of PAH by lowering the pressure in the lung arterioles. Moreover, the therapies that are successful in lowering mean Pulmonary Artery Pressure (PAP), do not prevent right heart failure and subsequent death. PAH medicine, that improve the survival of endothelial, vascular smooth muscle cells, and pneumocytes and to prevent further deterioration of the heart pump, are currently not available.

The central hypothesis is that accumulation of ceramide sphingolipids promotes the state of senescence and plexi-form lesions. The collaborative study, led by Mount Sinai genetics and cardiology teams are pursuing an approach that supplements a ceramide metabolizing enzyme, that revert senescent cells back to normal function.

A preliminary study used aerosol lung administration of a synthetic adeno-associated virus to deliver the gene cassette and test the therapeutic potential of this gene therapy for PAH in vivo. The positive outcomes exceeded expectations and demonstrated complete lung recovery following administration of the therapeutic.

In addition to PAH, AC gene transfer has been demonstrated as an effective solution to prevent cardiac damage following severe MI, which was evaluated in small and large animal models.

Stage of Development

Validated to completely preserve cardiac tissue and function in a large animal model (sheep) of severe MI
Validated in animal model (rat) of PAH
Evaluating AC gene transfer in clinical trial of dogs with PAH

Benefits

Improves hemodynamics in PAH and MI models
- Increases cardiac output and right ventricular ejection fraction
- Decreases right ventricular systolic volume, pulmonary artery pressure, and vascular resistance
Reduces scar tissue formation post inflammation
Reverses cell senescence and improves the survival of endothelial, vascular smooth muscle cells, and pneumocytes
Synthetic adeno-associated viral vector allows for rapid expression of AC

Applications

Prevention of cardiac damage following severe MI
Prevention or treatment of pulmonary hypertension
Human or animal applications
Other senescence-driven related disorders

Acid Ceramidase Gene Therapy for the Treatment of Pulmonary Hypertension and Cardiovascular Disease

Patents

IP Status

Seeking