Removing Junk from Between Cells
Extracellular aggregates are a category of damaged proteins that no longer serve their function, but instead have been warped into sticky, malformed conformations that on to the outside of our cells and tissues and impair their function. (These kinds of extracellular junk are different from extracellular cross-linking, which is a form of damage in which chemical links bind structural proteins together with each other, impairing their ability to move freely). Most such extracellular junk is termed “amyloid” of one variety or another.
The most well-known form of extracellular junk is beta-amyloid: the stifling, web-like material that forms both visible plaques and insidious, soluble “oligomers” in the brains of patients with Alzheimer’s disease, and also (more slowly) in everyone else’s with age, and often impairs cognitive function. Many other extracellular aggregates comprised of different malformed proteins accumulate in other tissues with age, and contribute to diseases of aging afflicting those tissues. For instance, Islet Amyloid Polypeptide (IAPP) forms in pancreas of people with Type II diabetes and other aging people, and impairs those cells’ ability to produce the hormone insulin, which is needed to control blood sugar. After being released into the circulation, IAPP also accumulates on cells of the heart, and may contribute to declining heart function in diabetes and with age. TTR amyloid, which forms out of transthyretin (TTR — a protein needed to transport thyroid hormone and other substances) accumulates in the heart with age (more quickly in people with specific TTR gene mutations), and is a major contributor to specific forms of heart failure, and also contributes to spinal stenosis and carpal tunnel syndrome. In fact, there is some evidence that “senile cardiac amyloidosis” driven in large part by TTR amyloid may be the main cause of death in people who survive beyond age 110.
Neuron and Microglia with Beta-Amyloid Plaque and Oligomers
The Rejuvenation Biotechnology Solution
Extracellular aggregates can be removed from the brain and other areas of the body by specialized antibodies that hone in specifically on them and remove them from the tissue. Such antibodies can either be produced in the patient’s own body using a procedure similar to vaccination, or they can be produced external to the body and infused. In the vaccination strategy, doctors inject small fragments of the targeted amyloid (or genetic instructions so a person’s cells temporarily produce the amyloid themselves, as with the mRNA vaccines that have figured prominently in fighting the COVID-19 pandemic. Exposure to the amyloid in this form stimulates the immune system to produce antibodies that target the amyloid and remove it. In the infusion therapy, therapeutic antibodies are pre-made in bioreactors and injected into the circulation, where they go straight to work targeting the amyloid. A prominent recent parallel to this is cocktails of monoclonal antibodies like Regeneron’s REGN-COV2, which prevent early-stage COVID-19 infections from escalating into life-threatening illness.
an extremely promising variation of the infused antibody approach has been developed by Dr. Sudhir Paul, then at the University of Texas-Houston Medical School. Dr. Paul discovered a subset of human antibodies with catalytic activity against their target antigens. Conventional antibodies targeting extracellular aggregates bind to their target, and then have to either hand it over to immune cells for destruction, or drag it to the liver and kidneys for removal. But catalytic antibodies (“catabodies”) destroy the amyloid directly, cleaving it into smaller, harmless fragments, right on the spot.
Catabodies offer important potential advantages over the binding antibodies used in other amyloid-targeting immune therapies. One is that it is expected to reduce the dose needed to effectively clear extracellular aggregates from tissues. This is because binding antibodies can only trap one molecule of amyloid, whereas once a molecule of catabody is done slicing its way through one molecule of amyloid it can move onto the next, again and again, allowing each molecule of catabody to quickly destroy multiple amyloid molecules.
A second advantage is that in order to get rid of their cargo, most binding antibodies need to drag their captured beta-amyloid across the protective barrier that shields the brain. This passage of a large antibody-amyloid complex is likely difficult, and is likely one of the reasons why minor damage to brain blood vessels and swelling of the brain have been observed in some patients receiving binding antibody therapies. Catabodies avoid this problem entirely by destroying their target on-site, leaving only small fragments behind that can likely be passively degraded.
Where We Are Now
Aducanumab (brand name Aduhelm®), the first infused antibody therapy targeting beta-amyloid, has already passed Phase III clinical trials and is conditionally licensed for use in patients with Alzheimer’s disease. With its decision, FDA opened an “accelerated approval” pathway for these therapies, based on evidence of damage removal and some evidence of a clinical benefit, though the company that makes Aduhelm must now complete an additional trial to prove definitively that it can improve cognitive function or other outcomes that matter to patients. In the wake of this decision, several other such therapeutic antibodies are now rushing toward Phase III trial, and some of these are even more promising than Aduhelm.
Rejuvenation biotechnologies targeting other extracellular aggregates are in much earlier stages of development.
SENS Research Foundation Research
SRF funded promising rejuvenation research in Dr. Paul’s laboratory to develop a catabody targeting TTR amyloid. After first identifying a TTR-cleaving catabody candidate derived from patient blood, his lab honed this candidate into two powerful improved versions, which break down TTR amyloid an astounding 500 times faster than the best of the patient-derived candidates! Based on the catabodies’ rapid kinetics and anticipated half-life in the blood, the researchers project that each one of these new catabodies could buzzsaw its way through more than 40,000 misfolded TTR molecules before they are themselves eliminated by physiological processes.
Importantly, none of these catabody candidates cleaved TTR in its healthy, normal conformation, nor a selection of 14 other physiologically important proteins. And the concentrations required to disintegrate 80% of a sample of TTR amyloid were many hundreds of times lower than those routinely achieved in the blood with other infused therapantibodies (such as REGN-COV2 or antibody-based treatments for patients with autoimmune disorders).
Although originally identified and harnessed for targeting extracellular aggregates, SENS Research Foundation scientists recently devised a new strategy to direct catabodies into the cell, where they could potentially target intracellular aggregates; Dr. Amit Sharma is now working to develop this strategy in our Research Center.