Question of the Month #9: What is the role of novel diagnostics in rejuvenation biotechnologies?
Q: I'm a biotech graduate currently reading up to produce a PhD proposal. My main areas of interest are in diagnostics, and after reading about rejuvenation biotechnology I’ve become very interested in contributing to regenerative medicine against ageing. Is there a crossover between diagnostics and the work under SENS Research Foundation? If so I'd love to hear about it.
A: There is definitely a need for novel diagnostics, particularly in the course of the critical three decades ahead, as the first rejuvenation biotechnologies enter into human clinical use.
As you probably know, rejuvenation biotechnologies are therapies that prevent, arrest, and potentially reverse age-related disease and dysfunction using a “damage-repair” approach. Such therapies work by directly removing, repairing, replacing, or rendering harmless the cellular and molecular damage wrought in our tissues by the biological aging process. This contrasts rejuvenation biotechnology with today’s medical approach, in which the target is the metabolic pathways that contribute to such damage instead of the damage itself. Current medicines are thus typically first tested for their effects on the metabolic “risk factors” that ultimately contribute to diseases of aging.
Rejuvenation biotechnologies, by contrast, will not directly perturb these metabolic processes (although in some cases they may maintain or restore metabolic processes in youthful condition, when aging normally leads to their dysfunction). Effects on these “risk factors” will therefore either be nonexistent, or manifest themselves many years later, when recipients continue to exhibit youthful metabolic function, in contrast to the age-related aberrations that emerge in untreated aging persons.
All this means that new ways of evaluating these novel medicines will be needed — first for their initial preclinical and clinical development, and later for their clinical use. Instead of reflecting dynamic, regulated physiological and metabolic processes, diagnostics that will facilitate the development and use of rejuvenation biotechnology will be noninvasive markers of the presence, removal, or repair of the cellular and molecular damage that accumulates in aging tissues.
One category of diagnostic that will be useful throughout the preclinical and clinical testing of new “damage-repair” therapies, and also for later clinical use, is assays that reflect in real time the repair or removal of the particular form of cellular or molecular damage targeted by a given rejuvenation biotechnology. Historically, the question of basic efficacy as a damage-repair agent per se has been evaluated in animal models through necropsy studies. This is fine for preclinical screening, but can provide only limited and delayed information during human trials, and is obviously useless in the clinical context. In the Phase I and Phase II clinical trials of the first vaccine therapy targeting beta-amyloid (AN1792), for instance, the vaccine’s ability to clear beta-amyloid out of the brain was impossible to evaluate over the course of the trial. It was only through the autopsy of participants in these studies who died during or after the course of the trial that this basic and critical information could be gleaned — and that, only slowly over the course of several years. Clearly, this type of assay, regardless of its scientific value in the post-mortem case, cannot provide information on how well a therapy is working in a living person who actually stands to benefit.
Much more useful would be noninvasive markers of rejuvenation biotechnologies at work clearing damage from aging tissues. Such markers would be invaluable throughout the development cycle and in clinical practice when new medicines are actually being used to rejuvenate individual aging persons. I.e., in Phase I testing, they would be used in order to determine target engagement and removal of damage from the relevant tissue; during Phase I/II dose-ranging studies they would help determine the dose(s) for late-stage clinical trials that best balances safety with maximum damage clearance; they would provide ongoing monitoring of efficacy in patients during Phase III trials; and ultimately, once rejuvenation biotechnologies are widely available, they would enable clinicians to effectively adjust dosages for individual patients.
Another helpful class of diagnostics would simply evaluate the level of burden present in a tissue at a given time. This is closer to the classical definition of a “diagnostic,” and in some cases could be used to diagnose a recognized clinical disease for which FDA and other regulators will license a drug. These diagnostics would help to identify the best candidates to enroll in clinical trials, which is especially important for those diseases of aging principally driven by different specific forms of accumulating damage but difficult to distinguish from one another on the basis of symptoms alone.
In the trials of the beta-amyloid-targeting passive vaccine bapineuzumab, for instance, it was only discovered once the trials were well underway that the cognitive impairment suffered by nearly a third of patients enrolled in the trial did not have the levels of beta-amyloid plaque accumulated in their brains that are the gold standard for diagnosing Alzheimer’s disease1. Instead, their cognitive dysfunction was being driven by some other form of aging damage, such neurofibrillary tangles, or Lewy bodies and other intracellular α-synuclein aggregates, or the damage to the brain from multiple small strokes.
Of course, even the more modest accumulation of beta-amyloid in these individuals’ brains was contributing at some level to cognitive dysfunction, and would eventually progress to levels characteristic of Alzheimer’s if the patients were not killed by something else first. But the fact that these persons had already entered into the early stages of dementia for reasons principally not related to beta-amyloid necessarily meant that even a highly effective beta-amyloid clearance therapy would have been insufficient to rescue their brains from ongoing neurodegenerative processes driven by far more severe and uninterrupted accumulation of other forms of damage.
Furthermore, the best people in whom to test rejuvenation biotechnologies are not people whose clinical state is as severe as participants in the bapineuzumab or AN1792 trials, even if every one of them were carefully selected for beta-amyloid-driven disease. Instead, it is best to test such therapies in persons whose cognitive processes are only very subtly disturbed and whose burden of damage — although biased toward one specific dominant neuropathological culprit — is still relatively low, and only approaching the level at which symptoms become obvious enough for the clinical diagnosis of a particular disease. If the burden of damage in the trial participants is too high, then it is possible that a particular rejuvenation biotechnology will simply not be able to clear damage quickly enough to save them from the fate that degenerative aging has in store for them. But if the level of damage is too low, then the long and insidious forces of aging will take many, many years to manifest in untreated persons — and thus, before the benefits of clearing that very small level of damage out of the tissue to become evident by comparison.
Later, once a given rejuvenation biotechnology is licensed and brought into clinical use, clinicians will need to use these novel diagnostics to decide when an individual aging person should first begin therapy with a given rejuvenation biotechnology, how aggressively to apply this therapy, and how often to initiate new rounds of treatment. At this stage, the relationships amongst the absolute burden of damage in a given person’s tissues; the rate at which a given dose of a particular rejuvenation biotechnology repairs or removes that damage; and the regimen that will most effectively restore and maintain healthy functioning at the levels typical of young adulthood should become much easier to understand and build upon.
Some particular novel diagnostics could take the form of methods of imaging the targeted damage. For example, researchers running the current clinical trials of aggregate-clearing vaccines in early and preclinical Alzheimer’s disease today are using new radiolabels against beta-amyloid and aberrant tau species in the brain. Others could be markers of damage mobilization out of the target tissue into biological fluids, including as plasma, cerebrospinal, or urine degradation products of such damage. Again, there are examples of such biomarkers already in use in trials of aggregate-clearing rejuvenation biotechnologies intended to prevent and reverse Alzheimer’s and Parkinson’s diseases.
As for SENS Research Foundation’s current activity in this area: we are, for instance, funding research for a new diagnostic for senile systemic amyloidosis. In this underdiagnosed disease of aging, the protein transthyretin (TTR, which transports vitamin A and thyroid hormones in the blood) twists out of its proper shape and forms insoluble deposits that infiltrate the heart and other organs. The insidious effects of TTR amyloid remain mostly silent until after middle age, but become sufficient to impair heart function in 20-25% of individuals over the age of 80, and apparently become a major contributory factor in the deaths of “supercentenarians” (persons who achieve 110 years or more of life).
Unfortunately, the existing standard diagnostic methods for senile systemic amyloidosis are either nonspecific (based on imaging) or highly invasive and specialized (cardiac biopsy), and its symptoms are very similar to other stiffening or overgrowth and weakening of the heart muscle caused by other things (such as the long-term effects of high blood pressure on the heart). As a result, senile systemic amyloidosis is often misdiagnosed, leading to inappropriate treatment for the wrong disease even as amyloid continues to build up in the patient’s heart and impair its function.
For this reason, we have invested funds in the laboratory of Brian O'Nullain at Harvard to develop diagnostic antibodies targeting wild-type TTR aggregates2 alongside the research dollars directed to Sudhir Paul’s research on developing catalytic antibodies to degrade those aggregates at the University of Texas-Houston Medical School3.
Further on into the future, as the panel of SENS therapies becomes more comprehensive and well-established, and as the therapies become safer and more effective, the need for these novel diagnostics may wane. After all, we all accumulate aging damage in our tissues, with lifestyle and genetics dictating only modest variations in the rate at which individuals reach critical levels of particular forms of that damage. At some point, doctors may begin administering rejuvenation biotechnologies to all of their patients on a relatively standardized regimen, secure in the knowledge that the schedule and doses they administer will be both safe for their patients and sufficient to clear keep the burden of damage down to levels similar to early middle adulthood. At that point, it will be in our power to hold degenerative aging and its disease and debility at bay on a “cookbook medicine” basis (similar to how we presently administer vaccinations and boosters that protect against infectious disease), with no need to recruit and monitor patients on an individual basis. But for the next few decades, novel diagnostics will indeed be key to the rapid progress toward a future of increased healthy lifespan.
- Vellas B, Carrillo MC, Sampaio C, Brashear HR, Siemers E, Hampel H, Schneider LS, Weiner M, Doody R, Khachaturian Z, Cedarbaum J, Grundman M, Broich K, Giacobini E, Dubois B, Sperling R, Wilcock GK, Fox N, Scheltens P, Touchon J, Hendrix S, Andrieu S, Aisen P; EU/US/CTAD Task Force Members. Designing drug trials for Alzheimer's disease: What we have learned from the release of the phase III antibody trials: A report from the EU/US/CTAD Task Force. Alzheimers Dement. 2013 Jul;9(4):438-44. doi: 10.1016/j.jalz.2013.03.007. PubMed PMID: 23809364.
- Phay M, Blinder V, Macy S, Greene MJ, Wooliver DC, Liu W, Planas A, Walsh DM, Connors LH, Primmer SR, Planque SA, Paul S, O'Nuallain B. Transthyretin aggregate-specific antibodies recognize cryptic epitopes on patient-derived amyloid fibrils. Rejuvenation Res. 2014 Apr;17(2):97-104. doi: 10.1089/rej.2013.1524. PubMed PMID: 24164623.
- Planque SA, Nishiyama Y, Hara M, Sonoda S, Murphy SK, Watanabe K, Mitsuda Y, Brown EL, Massey RJ, Primmer SR, O'Nuallain B, Paul S. Physiological IgM class catalytic antibodies selective for transthyretin amyloid. J Biol Chem. 2014 May 9;289(19):13243-58. doi: 10.1074/jbc.M114.557231. Epub 2014 Mar 19. PubMed PMID: 24648510; PubMed Central PMCID: PMC4036335.