Newswise — Pulmonary arterial hypertension (PAH) is a rare and incurable disease of the lung arteries that causes early death. In PAH, excess scar tissue and thickening of lung blood vessels occur as the result of increased cell “biomass.” These changes obstruct blood flow and are detrimental to the heart, but until now the basic features of biomass in PAH were not known. A team led by investigators at Brigham and Women’s Hospital (BWH), a founding member of the Mass General Brigham healthcare system, in collaboration with Matthew Steinhauser, MD, a metabolism and cell imaging expert at the University of Pittsburg, and investigators at the University of Vienna, set out to better understand the origins of arterial biomass in PAH. Using an animal model of PAH, the team applied network medicine and advanced molecular imaging tools to identify chemical building blocks that are taken up by arterial cells and ultimately contribute to blood vessel obstruction. Using multi-isotope imaging mass spectrometry (MIMS) under the guidance of Steinhauser and Christelle Guillermier, PhD, at BWH, the researchers could pinpoint the location and abundance of key contributors to biomass, including the amino acid proline and the sugar molecule glucose. Using MIMS, the team visualized proline and glucose tracers injected into the bloodstream of an animal model of PAH. They saw that the molecules were used by arterial cells of the lung to build excess scar tissue (including the protein collagen), which contributed to blood vessel obstruction. 

“Our study describes the world’s first use of multi-isotope imaging mass spectrometry (MIMS) in the study of lung disease,” said Bradley Wertheim, MD, of the Brigham’s Division of Pulmonary and Critical Medicine. “MIMS is a powerful microscopy tool that produces a ‘molecular snapshot’ that can provide information down to the resolution of a single cell.” 

“These findings suggest that the uptake and metabolism of protein precursors may be fundamental to PAH biology.  Closer investigation of proline and glucose in human PAH may uncover opportunities to inhibit biomass formation, prevent obstruction of lung arteries, and decrease the chance of heart failure for PAH patients,” said co-senior author Bradley Maron, MD, of the Brigham’s Division of Cardiovascular Medicine.

Read more in JCI Insight.

Source: Brigham and Women’s Hospital

Breakthrough offers a potential target for patients with heart failure

Newswise — An anti-ageing gene discovered in a population of centenarians has been shown to rewind the heart’s biological age by 10 years. The breakthrough, published in Cardiovascular Research and led by scientists at the University of Bristol and the MultiMedica Group in Italy, offers a potential target for patients with heart failure.

Associated with exceptional longevity, carriers of healthy mutant genes, like those living in blue zones of the planet, often live to 100 years or more and remain in good health. These individuals are also less prone to cardiovascular complications. Scientists funded by the British Heart Foundation believe the gene helps to keep their hearts young by protecting them against diseases linked to ageing, such as heart failure.

In this new study, researchers demonstrate that one of these healthy mutant genes, previously proved particularly frequent in centenarians, can protect cells collected from patients with heart failure requiring cardiac transplantation.

The Bristol team, led by Professor Paolo Madeddu, has found that a single administration of the mutant anti-ageing gene halted the decay of heart function in middle-aged mice. Even more remarkably, when given to elderly mice, whose hearts exhibit the same alterations observed in elderly patients, the gene rewound the heart’s biological clock age by the human equivalent of more than ten years.

Professor Madeddu, Professor of Experimental Cardiovascular Medicine from Bristol Heart Institute at the University of Bristol and one of the study’s authors, explained: “The heart and blood vessel function is put at stake as we age. However, the rate at which these harmful changes occur is different among people. Smoking, alcohol, and sedentary life make the ageing clock faster. Whereas eating well and exercising delay the heart’s ageing clock.

“In addition, having good genes inherited from parents can help to stay young and healthy. Genes are sequences of letters that encode proteins. By chance, some of these letters can mutate. Most of these mutations are insignificant; in a few cases, however, the mutation can make the gene function worse or better, like for the mutant anti-ageing gene we have studied here on human cells and older mice.”

The three-year study was also performed in test tube human cardiac cells in Italy. Researchers from the MultiMedica Group in Milan led by Professor Annibale Puca, administered the gene in heart cells from elderly patients with severe heart problems, including transplantation, and then compared their function with those of healthy individuals.

Monica Cattaneo, a researcher of the MultiMedica Group in Milan, Italy, and first author of the work said: “The cells of the elderly patients, in particular those that support the construction of new blood vessels, called ‘pericytes’, were found to be less performing and more aged. By adding the longevity gene/protein to the test tube, we observed a process of cardiac rejuvenation: the cardiac cells of elderly heart failure patients have resumed functioning properly, proving to be more efficient in building new blood vessels.”

Centenarians pass their healthy genes to their offspring. The study demonstrates for the first time that a healthy gene found in centenarians could be transferred to unrelated people to protect their hearts. Other mutations might be found in the future with similar or even superior curative potential than the one investigated by this research. Professor Madeddu and Professor Annibale Puca of the MultiMedica Group in Milan believe this study may fuel a new wave of treatments inspired by the genetics of centenarians. 

Professor Madeddu added: “Our findings confirm the healthy mutant gene can reverse the decline of heart performance in older people. We are now interested in determining if giving the protein instead of the gene can also work. Gene therapy is widely used to treat diseases caused by bad genes. However, a treatment based on a protein is safer and more viable than gene therapy.

“We have received funding from the Medical Research Council to test healthy gene therapy in Progeria. This genetic disease, also known as Hutchinson-Gilford syndrome, causes early aging damage to children’s hearts and blood vessels. We have also been funded by the British Heart Foundation and Diabetes UK to test the protein in older and diabetic mice, respectively.”

Annibale Puca, Head of the laboratory at the IRCCS MultiMedica and Professor at the University of Salerno, added: “Gene therapy with the healthy gene in mouse models of disease has already been shown to prevent the onset of atherosclerosis, vascular ageing, and diabetic complications, and to rejuvenate the immune system.

“We have a new confirmation and enlargement of the therapeutic potential of the gene/protein. We hope to test its effectiveness soon in clinical trials on patients with heart failure.”

Professor James Leiper, Associate Medical Director at the British Heart Foundation, which funded the research, said: “We all want to know the secrets of ageing and how we might slow down age-related disease. Our heart function declines with age but this research has extraordinarily revealed that a variant of a gene that is commonly found in long-lived people can halt and even reverse ageing of the heart in mice.

“This is still early-stage research, but could one day provide a revolutionary way to treat people with heart failure and even stop the debilitating condition from developing in the first place.”

The study is funded by the British Heart Foundation and the Italian Ministry of Health.

Paper

‘The longevity-associated BPIFB4 gene supports cardiac function and vascularization in aging cardiomyopathy’ by Annibale Puca et al. in Cardiovascular Research [open access]

Source: University of Bristol

https://stmdailynews.com/category/lifestyle/health-and-wellness/health/

Newswise — BOSTON –A combination of two next-generation immunotherapy drugs has shown promising clinical activity in treating patients with refractory metastatic colorectal cancer, a disease which has not previously responded well to immunotherapies, according to a Dana-Farber Cancer Institute researcher.

The results of an expanded phase 1 trial of the two drugs, botensilimab and balstilimab, are to be presented at the ASCO Gastrointestinal Cancers Symposium Jan. 19-21 in San Francisco. The study is led by Benjamin L. Schlechter, MD, a senior physician in the Gastrointestinal Cancer Treatment Center at Dana-Farber.

The trial included 70 patients with metastatic colorectal cancer who had been previously treated with several lines of drugs, including immunotherapies. These patients all had tumors termed microsatellite stable, or MSS, meaning that their genes for repairing certain types of DNA damage were intact. MSS colorectal tumors account for the vast majority of colorectal cancers, and the first generation of immunotherapy drugs have had little effect on them. While immunotherapy has succeeded in microsatellite unstable (MSI) colorectal cancers, only about 3-5% advanced colorectal cancers are MSI and there are no approved immunotherapies for the far more common MSS colorectal cancers.

The two-drug combination being tested in the expanded phase 1a/1b trial of patients with metastatic MSS colorectal cancers were novel, next-generation antibodies. Botensilimab is an antibody directed against the T-cell receptor cytotoxic T-lymphocyte-associated antigen 4, or CTLA-4, which is an immune checkpoint that regulates T-cell activation. Balstilimab is a novel monoclonal antibody designed to block PD-1 – another immune checkpoint protein – from interacting with PD-L1 and PD-L2. By inhibiting this interaction, balstilimab is aimed at freeing the immune system to attack cancers.

The patients in the trial were followed for a median of 7 months after receiving the drug combination. During that period, 23% of the patients had a reduction in the size of their tumors, and the median duration of response was not reached. The disease control rate – the percentage of patients with metastatic cancer who had a complete or partial response and stable disease – was 76%. The 12-month overall survival was 63%. The main population of patients who benefited from the combination were those who did not have active metastatic cancer in their liver.

Treatment-related adverse events occurred in 91% of patients, including grade 3 in 40% and grade 4 in 3%. Twelve percent of patients discontinued both drugs because of adverse events.

The researchers concluded that “in patients with heavily pretreated metastatic MSS colorectal cancer, botensilimab plus balstilimab continues to demonstrate promising clinical activity with durable response, and was well tolerated, with no new immune-mediated safety signals.”

“Harnessing the power of immune therapy in refractory colorectal cancer has been a key goal of multiple clinical trials in advanced colorectal cancer, but in MSS colorectal cancer efforts have been universally disappointing,” said Schlechter. “These data are a meaningful and important advance in the care of this very sick population.” 

Based on these findings, a randomized phase 2 trial in patients with MSS colorectal cancer is currently enrolling.

Funding for this research comes from Agenus, Inc.

About Dana-Farber Cancer Institute 

Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. Dana-Farber’s mission is to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber is a federally designated Comprehensive Cancer Center and a teaching affiliate of Harvard Medical School.

We provide the latest treatments in cancer for adults through Dana-Farber Brigham Cancer Center and for children through Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Dana-Farber is the only hospital nationwide with a top 5 U.S. News & World Report Best Cancer Hospital ranking in both adult and pediatric care.

Source: Dana-Farber Cancer Institute 

https://stmdailynews.com/category/lifestyle/health-and-wellness/health/