Healthy longevity gene inspired therapy to rescue cardiovascular disease in progeria

Hutchinson-Gilford progeria syndrome (HGPS) is a rare disease caused by an abnormal gene and related protein. Due to the lack of an effective cure, children with HGPS, who have completely normal intellectual development, die of cardiovascular disease at the average age of ~14 years. This project proposes a new solution consisting of transferring a salutary gene that is found in healthy long-living individuals to rescue the premature cardiovascular senescence typical of HGPS patients. We will test the new treatment in mice affected by HGPS as an initial step before proposing a study in patients.

Our team has discovered a beneficial variant of the BPIFB4 gene, which associates with exceptional longevity and, even more importantly, with long-lasting health in some centenarians. Next, we demonstrated that the transfer of the BPIFB4 gene attenuates the suffering from a heart attack, diabetes, high blood pressure in animal models. Moreover, BPIFB4 gene therapy reduced frailty, atherosclerosis, and heart damage in very old mice. Preliminary studies showed that the longevity BPIFB4 mutation can benefit some molecular mechanisms that are dysfunctional in HGPS children.

We will determine the efficacy of BPIFB4 gene therapy in HGPS mice, looking at the treatment ability to preserve heart and blood vessel function. In addition, we will investigate the mechanisms underpinning the benefit, using human cells from HGPS patients.

If results are positive, we will continue our research confirming the lack of toxicity (the fact that the gene variant is associated with improved human health is already reassuring), defining the best dose/timing of treatment for prolonged benefit, and the advantage of adding BPIFB4 therapy to current drugs in view of obtaining permission for a clinical study in patients.

The study investigates the use of the longevity-associated variant of the human BPIFB4 gene (LAV-BPIFB4) for the treatment of cardiovascular complications of Hutchinson-Gilford progeria syndrome (HGPS).

The applicants showed that LAV-BPIFB4 gene therapy alleviates cardiovascular disease and atherosclerosis in animal models and provided extensive mechanistic insight into the pathways underpinning the therapeutic benefit. Pilot data indicate that there is a strong overlapping between the targets of LAV-BPIFB4 and progerin, thus suggesting LAV-BPIFB4 could rescue cellular dysfunction at multiple levels.

The experimental plan includes 3 WPs. In WP1, imaging studies using echocardiography and PET/CT scan will determine the efficacy of LAV-BPIFB4 gene therapy in progeric mice. In WP2, histology and immunohistochemistry analyses will be conducted in harvested murine cardiovascular tissues to verify the benefit of LAV-BPIFB4 gene therapy on the structural alterations that affect blood vessels and the heart. Moreover, we will assess the effect of therapy on the expression levels of BPIFB4/lamins in the heart and blood vessels. In WP3, we will analyse underpinning mechanisms in murine tissues and human HGPS cells. The simplification has resulted in ~ £40K saving as compared with the previous application. Ethical approvals and technical procedures are in place and the research environment is very supportive.