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EFFECTS OF ALZHEIMER’S GENE MIGHT BE REVERSIBLE
Scientists studying the strongest genetic risk factor for Alzheimer’s disease say they have new clues to how it works and how its damaging effects on the brain could potentially be reversed.
Doctors have long known that the brain’s blood vessels deteriorate with Alzheimer’s disease, particularly in people with the APOE4 gene, but the underlying mechanisms have remained unclear.
In fact, APOE4 damages the brain’s blood vessels and promotes the buildup of abnormal proteins, researchers at the Icahn School of Medicine at Mount Sinai in New York have discovered.
It does so by causing pericytes, cells that normally stabilize small blood vessels, to transform into scar-forming cells that thicken the vessels and increase the accumulation of abnormal, misfolded protein clumps known as amyloid, the target of current treatments. These conditions can compromise the flow of blood to the brain, leading to brain damage.
Blocking a protein called TGF-beta that is involved in tissue cell activity and repair protected the pericytes and reversed APOE4-associated cerebrovascular degeneration in mice, the researchers also discovered.
Their findings are reported in two separate papers in Cell and Cell Stem Cell.
“Damage to the brain’s blood vessels is not simply a late consequence of Alzheimer’s disease; it is a biologically active process caused by APOE4 that may be reversible,” Joel Blanchard, who co-authored both papers, said in a statement.
“These findings reveal new therapeutic targets for preserving vascular function and limiting amyloid accumulation.”
GILEAD THERAPY SHOWS PROMISE IN MULTIPLE MYELOMA TRIAL
An investigational CAR T-cell therapy from Gilead Sciences led to deep and durable responses in people with hard-to-treat or recurrent multiple myeloma in an early-stage trial, researchers reported in The New England Journal of Medicine.
Phase 1 trials are designed to test safety, not efficacy, so the promising results will require confirmation in larger trials.
But all 38 patients who received anitocabtagene autoleucel (anito-cel) responded to the treatment, and nearly 80% achieved a complete response, meaning no detectable cancer, the researchers said.
Many of the patients experienced lasting benefits, with more than half showing no sign of disease progression two years later and 65% still alive after three years.
Serious immune-related and neurological side effects were uncommon, and no delayed neurological complications were reported.
Anito-cel is a so-called B-cell maturation antigen, or BCMA-targeted CAR T-cell therapy, in which a patient’s immune system T cells are removed and engineered in a laboratory to locate and destroy cells expressing BCMA – a protein found in high amounts on the surface of multiple myeloma cells – before being reinfused.
“These were great results for a Phase 1 trial,” study leader Dr. Michael Bishop of UChicago Medicine said in a statement.
“Even at a low dose of anito-cel, we were seeing complete responses in the majority of patients right off the bat, and not a single patient developed severe toxicities.”
Anito-cel is currently being evaluated in Phase 2 and Phase 3 clinical trials to confirm these findings in larger populations of patients with multiple myeloma, the researchers said.
FINDING OLD CELLS THAT DON’T DIE WHEN THEY SHOULD
Researchers have found a noninvasive way to identify and study cells in the body that contribute to age-related disorders such as cancer, tissue degeneration, and inflammatory diseases.
These so-called senescent cells have stopped dividing and growing but for some reason have not died, as would be expected of old cells. Instead, they undergo significant changes to their shape, metabolic processes, and gene activity.
Earlier methods of studying these cells would destroy them, the researchers noted in a report of the study in Nature Aging.
Using an analytical technique known as Raman microscopy, which reveals the biochemical composition of cells without harming them, and analyzing individual cells’ genetic activity, the researchers were able to identify unique “barcodes” of senescent cells.
The study was done in mouse cells. The researchers are now working on adapting it for use with human tissue.
“You can imagine that one day we may develop an endoscope that can look inside your body and identify cellular senescence,” Jeon Woong Kang of MIT, one of the senior authors of the study, said in a statement.
Study leader Peter So of MIT noted that senescence “is not just a pathological condition.”
While it can also contribute to sagging skin and muscle weakness in aging individuals, cellular senescence plays critical beneficial roles in embryonic development and tissue regeneration, the researchers noted.
The research is part of a National Institutes of Health initiative called the Cellular Senescence Network.
“The idea behind the NIH Cellular Senescence Network is to take a very comprehensive approach to understand senescence and identify senescent cells, because it plays a role in so many normal physiological conditions and many pathological conditions,” So said.
