By Deborah Borfitz

June 29, 2020 | A 30-year-old clinical procedure could explode in popularity if its mouse equivalent holds true in humans—reduction in damaging proteins that have been implicated in diseases such as Alzheimer’s disease and heart failure. Therapeutic plasma exchange (TPE) is currently being used to treat more than 50 relatively uncommon diseases, primarily autoimmune disorders, but not more frequently occurring, age-related disorders, says Dobri Kiprov, M.D., medical director of Apheresis Care Group in San Francisco and an internationally recognized expert in the field.

Irina and Mike Conboy, both bioengineering experts at UC Berkeley, have been studying systemic aging and rejuvenation since early 2000s. Their seminal 2005 paper (DOI: 10.1038/nature03260) established that multiple old tissues become quickly and robustly rejuvenated when young and old mice are experimentally made into co-joined twins.

Their recent work on rejuvenation by plasma dilution (DOI: 10.18632/aging.103418) introduces an entirely new scientific paradigm that improving the health and function of multiple old organs doesn’t require complex approaches or the search for novel molecules. An equally if not more robust method is to replace a portion of blood plasma with saline and replenishing lost albumin.

Among the important findings is that “young” proteins, which are needed for tissue health and repair and become deficient with age, are restored when their age-elevated inhibitors are diluted, explains I. Conboy. In other words, the “bloodstream milieu is reset to youth and health” for both age-elevated and age-diminished determinants.

“It wasn’t that we added something that was an elixir,” says M. Conboy.

The clinical significance of this work is underscored by collaboration with Kiprov, who suspected TPE in people might be rejuvenative, continues I. Conboy. He provided the Conboy group with samples of human blood from patients who underwent the procedure.

After finding that plasma dilution significantly improved the health of old mice and made old human blood supportive for tissue repair, the researchers conducted a proteomic analysis of the blood plasma of the animals to find out how the proteins in their blood changed following the procedure. They performed a similar analysis on blood plasma from humans who had undergone TPE. In both cases, says I. Conboy, the plasma exchange process acted somewhat like a “molecular reset” button for health and youth.

Efficacy Trial Planned

The next step is to reposition TPE for preventing and treating diseases that affect people at an older age, Kiprov says, adding that he just completed a “very significant clinical trial” related to Alzheimer’s disease that looked at this question and is now in press. Among the unknowns to be tackled with the new, placebo-controlled study are how many TPE procedures are required to prevent a disease or stop its progression and if the protective effects are short- or long-lived.

As with many other planned trials, the start date of the phase II efficacy study has been delayed by the COVID-19 pandemic. But the protocol is written and has the approval of a national institutional review board, says Kiprov, who will be a clinical co-investigator on these trials.

Patients don’t have to be followed for years, as the goal and expectation is a rapid reversal of age-imposed diseases—including inflammatory, fibrotic, degenerative, and metabolic illnesses, says I. Conboy. A diagnosis of cancer might be one of the exclusion criteria.

“If we can prolong the healthspan of participants we can possibly prolong their lifespan because most people don’t die of old age but from disease,” Kiprov says. The study already has pilot funding and a list of people waiting to be enrolled.

Among the long list of potential enrollees are people with fibrosis disorders, diabetes, cirrhosis of liver and degenerative diseases such as muscle wasting, Alzheimer’s, and Parkinson’s, says I. Conboy. The plan is to start with about 50 patients at one clinic and see if, in addition to health improvements and functional rejuvenation, their blood develops a more youthful profile.

Admittedly, TPE can be an unpleasant experience because it’s a two-hour procedure that involves needle sticks in both arms, says Kiprov. But the computer-controlled apheresis machine is sophisticated and used by highly trained professionals. Side effects are mild and occur in only 3% to 4% of cases.

COVID-19 Connection

As Kiprov recently reported in a video blog, multiple clinical trials are underway to see if TPE can be used in the treatment of the overwhelming inflammatory response, or cytokine storm, seen in severe cases of COVID-19. TPE has been successfully used to treat cytokine storm in other medical conditions, including sepsis and cancer patients being treated with chimeric antigen receptor (CAR)-T cell therapy.

Similarly, infusion devices capable of removing cytokines in COVID-19 patients are being used in several clinical trials in the U.S. and Europe, he adds. These include CytoSorbents’ CtyoSorb and SeaStar Medical’s CLR system, both of which work in conjunction with continuous renal replacement therapy. A potential problem is obstruction of the filter by small thrombi in the circulation of many critically ill COVID-19 patients.

Terumo BCT also recently announced that its Spectra Optia Apheresis System is being combined with Marker Therapeutics’ D2000 Adsorption Cartridge to reduce cytokine levels in COVID-19 patients with confirmed or imminent respiratory failure.

It is no coincidence that the people hit hardest by COVID-19 are mostly elderly and have preexisting conditions, Kiprov says, as both the aging process and chronic diseases are associated with prolonged inflammation. When they’re infected with the virus, new pro-inflammatory factors join the already existing ones to bring on a cytokine storm that rapidly results in organ damage.

“The lungs are the primary target for this immune response, but no organ is spared,” says Kiprov. In fact, it has been observed that the kidneys are affected in between 30% and 60% of hospitalized COVID-19 patients.

Physicians have no more than 36 hours to initiate treatment if cytokine storm is suspected; organ damage will be permanent, if patients survive at all, once they’re intubated. The criteria used by Kiprov includes respiratory distress, elevated white blood cell count, low lymphocyte count, and high levels of C-reactive protein, ferritin, and lactate dehydrogenase (a biomarker of tissue damage), he shares in the video.

TPE with convalescent plasma for severe COVID-19 has been tried experimentally in China and more recently the U.S. and shown promising results when used early in the disease, Kiprov notes. Circulating immunoglobulin G antibodies in the plasma of people who have recovered from COVID-19 can provide “passive immunization” during the wait for an effective vaccine.

Eventually, convalescent plasma could be used to make coronavirus-specific antibodies, he says. Sorrento Therapeutics, for example, recently announced that it had developed a potent anti-SARS-CoV-2 antibody that has demonstrated its ability to inhibit infection in preclinical studies. The goal is an antibody cocktail that would provide a long-term, vaccine-like shield of protection.

No ‘Silver Bullets’

To date, the role of the Food and Drug Administration with TPE has been in approving the machine used to separate blood into its different parts and then remove and replace most of the plasma. Physicians decide when to order the treatment and in general follow the recommendations of various medical societies, Kiprov says. The American Society for Apheresis, for its part, issues clinical guidelines that puts diseases into one of three categorizes based on the strength of the evidence supporting TPE use.

Its first effective use was in the late 1970s for Waldenström's macroglobulinemia, predominantly a disease of elderly white men characterized by an overproduction of large proteins called immunoglobulins that interfere with blood circulation, causing hyperviscosity, says Kiprov. The blood of some patients can become as thick as jelly.

TPE proved to be quite good at clearing out antibodies that promote autoimmune diseases and inflammation, he continues. They’re less efficient at depleting small molecules, such as cytokines, whose function are less defined but are in plentiful supply in the circulation of patients with autoimmune diseases.

The 2005 Nature paper set off a flurry of research into whether the blood of young mice might serve as a "fountain of youth" for the old mice—and the compelling possibility that the same might hold true in humans, says I. Conboy. What many overlooked in that report, which her group has replicated in a more recent study, is that exchanging blood between young and old animals without physically joining them ages the young mice. That means young blood circulating through young veins couldn’t compete with old blood.

Research enthusiasm around the idea that young plasma contains “silver bullets” for aging has been hard to dampen, says Kiprov. But he remains hopeful that the more recently published findings will divert attention to plasma exchange for both combatting aging and promoting productive immunomodulation.

While TPE may seem like a simple concept, says I. Conboy, repositioning it for new classes of age-related disorders would not be effective or safe without dedicated clinical trials. She has also launched a biotech company, IMYu, where the R&D focus will be on understanding how “designer TPE” simultaneously rejuvenates multiple tissues and then applying that knowledge to the development of next-generation anti-aging therapeutics.