MedicalResearch.com: What is the background for this study?
Response: Our research is aimed to develop novel therapeutics for age-related disorders from fundamental understandings of blood plasma. This expands upon work initially performed in the Wyss-Coray lab at Stanford utilizing a model of parabiosis. By surgically conjoining the blood supplies between a young and aged mouse, they established that beneficial effects were observed in the aged mouse brain, suggesting that there are proteins in young blood which have enhancing properties.
The research presented at AAIC was the culmination of several years of model and dosing paradigm development utilizing both human plasma and a proprietary fractionated plasma product leading to advances for clinical application.
MedicalResearch.com: What are the main findings?
Response: We initially performed work in aged immunocompromised mice as intravenous injection of human proteins in plasma can trigger immune reactivity in immunocompetent animals. Having determined through several small histology-based studies that dosing could be optimized to induce long-term effects, we initiated several larger scale studies to evaluate additional endpoints. Through cognitive behavioral testing in aged mice, we observed significant improvement with this dosing regimen with both young human plasma and a human plasma fraction in a hippocampus-dependent spatial memory assay. Timing of this correlated to significant increases in neurogenesis.
By labeling mouse hippocampal progenitor cells prior to intravenous plasma and plasma fraction injections in these animals, we were able to determine that there was significant increase in survival of these cells. We didn’t observe any increase in neurogenesis or cell survival with mice injected with aged human plasma indicating that enhancement was not occurring due to administration of proteins contained in aged human plasma into mice, and benefits are conferred by the protein milieu of young plasma or the plasma fraction. We also investigated progenitor cell differentiation, observing a significant skewing towards neuron formation instead of astrocytes within the dentate gyrus with the plasma fraction, yet another reversal of effects commonly observed in normal aging.
To establish a better understanding of how prolonged these effects are, we investigated brain histology months after completion of pulse dosing and observed significant increases in neurogenesis and cell survival with only the animals which were administered the plasma fraction. To ensure these findings were age-related, we investigated effects from the human plasma fraction in several younger aged mouse cohorts and determined that effects are more pronounced at older ages, suggesting that the plasma fraction is enhancing the neurogenic niche and providing trophic support as endogenous support has declined. As this plasma fraction has reduced immunogenic properties due to removal of factors through the fractionation process, we investigated its effects in aged WT mice to allow for future investigation in disease and transgenic animal models.
It proved to be safe, and in addition, we observed significant increases in neurogenesis, cell survival as well as significantly decreased hippocampus inflammation and a significant acute increase in pre-frontal cortex activity.
MedicalResearch.com: What should readers take away from your report?
Response: The Alzheimer’s field has focused primarily on therapeutics targeting the removal of A-beta and Tau, but new approaches are required as preclinical treatment of disease pathophysiology has not translated to improved clinical outcomes.
Here we present a novel therapeutic treatment approach which shows great promise in counteracting the effects of aging within the brain. Foundational preclinical data with plasma has been encouraging, but as a therapeutic, plasma itself poses issues with clinical viability and feasibility. We have identified an advantageous, proprietary, plasma fraction and our ongoing clinical trials will evaluate whether this plasma fraction has efficacy in Alzheimer’s disease. The potential for utilization as stand alone or in combination therapy for diseases of aging and neurodegeneration by enhancing the neurogenic niche is incredibly exciting.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: We are investigating many different plasma derived products and specific plasma proteins which change during the normal aging process, we intend to determine what protein or protein milieu are responsible for the effects we are observing and derive new products based on our findings.
MedicalResearch.com: Is there anything else you would like to add?
Response: I would like to thank the entire team at Alkahest for their work on this project, and the support of Grifols
Disclosures: I am an employee of Alkahest
Citation: Presented at 2018 AAIC meeting July 2018
Beneficial Properties of a Human Plasma Fraction for Age-Related Cognitive Disorders
Gallager, I; Castro, M; Alcantara-Lee, R; Estrada, R; Kheifets, V; Czirr, E; Minami, S; Braithwaite, S;
Alkahest Inc. San Carlos, CA
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