AmyloSENS at Brigham & Women's Hospital

 

Removing extracellular aggregates

Aging bodies slowly accumulate extracellular aggregates around their cells: sticky clumps of proteins that interfere with cells and tissues carrying out their function.  Two such proteins are responsible for age-related disorders in heart function: the "cardiac amyloidoses", senile systemic amyloidosis (SSA) and isolated atrial amyloidosis (IAA). Removing these aggregates is necessary to rejuvenate the structure and function of the aging heart. 
 
To carry out their healthy function, proteins must maintain their complex three-dimensional shape. However, some such proteins are vulnerable to damage that can warp them out of these shapes, and many of the resulting malformed proteins form extracellular aggregates (also known as amyloids): sticky clumps of proteins that bind together into constricting webs that are deposited around cells and tissues and interfere with their normal function.  Such proteins are formed throughout the life, but only slowly accumulate in the body, so that their pathological effects only become clear after many decades of life gives time for the burden of such proteins to reach pathological levels.
 
The most famous of these is beta-amyloid protein, which is an important pathological feature of Alzheimer's disease. Less well-known are the aggregates that cause age-related disorders in heart function: the "cardiac amyloidoses", senile systemic amyloidosis (SSA) (caused by aggregated wild-type transthyretin (TTR)) and isolated atrial amyloidosis (IAA) (caused by aggregated atrial natriuretic peptide (ANP)). While very few people in middle age and early seniority have significant damage to heart structure and function from these diseases, the problem becomes more common after the age of 60, reaching 25% of persons over the age of 80 and becoming perhaps the most important cause of death at the extremes of the current human lifespan.
 
A comprehensive suite of rejuvenation biotechnologies must therefore include medical therapies to remove these aggregates. SRF is now funding Drs Sudhir Paul at the University of Texas-Houston Medical School and Brian O’Nuallain at Brigham & Women's Hospital at Harvard University in a collaborative effort organized by the Supercentenarian Research Foundation (SRF)'s Stan Primmer to begin the development of such therapies for SSA. Dr. O'Nuallain will use his expertise with binding antibodies against amyloids to create a diagnostic antibody that will readily detect the presence of such aggregates: SSA is very difficult to diagnose current techniques, and as a result it is often misdiagnosed and, unfortunately, mistreated by doctors. Meanwhile, Dr. Paul will focus his efforts on developing a catalytic antibody fragment to break them apart at the molecular level. Dr. Paul has already identified and optimized antibody fragments that destroy beta-amyloid protein, and is advancing them through the therapeutic pipeline; with SENS Research Foundation support, he will now use the experience and technology base he developed in that process to develop similar antibody fragments to clear the aging heart of TTR amyloids, restoring youthful structure and function.