Novel Abeta Vaccine Reports First Human Data

SENS (Strategies for Engineered Negligible Senescence) — SENS approaches the diseases and disabilities of aging from an “engineering” point of view. Instead of seeking to decipher the code of life and interfere with metabolic processes (the gerontological approach), or waiting until it is effectively too late to treat age-related damage and treating symptoms (the conventional medical, geriatric approach), SENS targets the damage of aging itself, bringing it down to levels below the threshold at which it causes problems.

With promising preliminary human data and what appears to be a mechanism of Aβ clearance, the advancement of gantenerumab into preliminary efficacy testing places one more damage-removal therapeutic into the race for disease-modifying therapies for AD. Should it ultimately be successful and its migroglial cell-mediated mechanism of action be validated, it would have the advantage of being potentially in synergy with lysosomal fortification with novel hydrolases to enhance microglial lysosomal hydrolysis of engulfed Aβ.

Rejuvenation biotechnology is the application of the principles of regenerative medicine to the damage to cellular and molecular structures that accumulate in aging tissues — the structural damage that disables those structures’ function and leads to loss of homeostasis and the progressive rise in frailty, disease, disability, and death that people now suffer with age. Because the damage is multifarious, a platform of rejuvenation biotechnologies, rather than a single, all-encompassing “youth pill,” will be required to achieve the robust rejuvenation of aging humans, restoring youthful health and vitality.

SENS is a strategy for engineering negligible senescence, based on this heuristic — not a prescriptive list of therapies in development whereby it shall be executed. The rapidly-expanding group of agents, each with a meaningfully-distinct mechanism of Aβ clearance, entering into the clinical pipeline and in increasingly advanced stages of human clinical testing for the arrest and reversal of Alzheimer’s disease, bodes well for the early achievement of the first rejuvenation biotechnology. SENS Foundation is proud to be engaged in its mission of catalyzing the progress toward a mature rejuvenation biotechnology industry; with that proof of concept, the wider biomedical field should become more alive to the application of the damage-removal heuristic to the many different kinds of aging damage underlying age-related disease. The engagement of a wide range of scientists in academia and industry, and aggressive funding of rejuvenation research, will accelerate progress toward a comprehensive panel of rejuvenation biotechnologies, and the achievement of thoroughgoing biomedical restoration of youthful health, vigor, and longevity.

The theoretical advantages of catalytic antibodies as a mechanism for the therapeutic clearance of malformed protein deposits, combined with promising results to date in preclinical studies using such antibodies to clear brain Aβ, were key considerations leading to SENS Foundation’s funding of research into catalytic antibodies for the removal of senile cardiac amyloidosis.

Accumulation of soluble and insoluble aggregates of beta-amyloid protein (Aß) and other malformed proteins accumulate in brain aging and neurodegenerative disease, leading progressively to neuronal dysfunction and/or loss. These have long been widely accepted to be drivers of Alzheimer’s disease (AD) and other age-related dementias and neurological disorders such as Parkinson’s disease, and it has recently become increasingly clear that neuronal protein aggregates are the main driver of “normal” cognitive aging. To prevent and reverse the course of neurodegenerative disease and age-related cognitive dysfunction, the regenerative engineering solution is therapeutic clearance of extracellular aggregates (such as Aß plaques) and intracellular aggregates (such as soluble, oligomeric Aß).

The reason for the early termination of the trial was — unfortunately but not unexpectedly — the appearance of an adverse reaction in the high-dose gantenerumab group: MRI revealed that 2 subjects underwent transient periods of focal cerebrovascular inflammation or vasogenic oedema, coinciding with sites with the greatest local clearance of Aβ deposits.(3) Their appearance, while not welcome, would have been anticipated, based on their earlier occurrence in Phase II trials with bapineuzumab(4) and possibly solanezumab,(5) but ongoing study of these “amyloid-related imaging abnomralities” (ARIA)(11) now suggests that they are less concerning than they had initially appeared. Data from cerebral imaging studies of the general, non-AD population of Rotterdam show that haemosiderin abnormalities (ARIA-H) consistent with cerebral microbleeds occur in 3-15% of older adults,(6) and several studies presented at the 2011 Alzheimer’s Association International Conference (AAIC, formerly ICAD) suggest that vasogenic oedema (ARIA-E) may also be common in untreated subjects with the disease. In fact, reports there and elsewhere (including preclinical studies on the mechanism of such abnormalities, and a central blinded review of sequential brain images from the Phase II bapineuzumab trial) suggest that their increased occurrence in patients treated with Aβ-binding therapeutic antibodies is not only relatively mild and transient, but a potentially positive rough indicator of successful mobilization of brain Aβ.*

The combination of initial, dose-dependent reduction of brain Aβ as detected on PiB-PET, plus (ironically) the occurrence of vasogenic oedema at locations adjacent to the sites where clearance is greatest, is tantalizing evidence that gantenerumab is efficacious in removing these malformed proteins from the brain. The study was too small and early-phase to permit assessment of cognitive outcomes, but with the success of the Phase I trial, a Phase IIb clinical trial is now underway, which will test the effects of subcutaneous gantenerumab (225 or 105 mg every 4 weeks for 104 weeks) vs. placebo on cognitive and functional outcomes in subjects with prodromal AD (identified based on partner-observed, gradual reductions in memory and cerebrospinal fluid biomarkers, but without dementia

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