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A Stem-Cell-Derived Cell-Free Therapy for Stroke: Moving Conditioned Medium into Clinical Trial

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Cell Therapy for Brain Injury

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Abstract

Stem cells have demonstrated promise in early clinical trials evaluating safety, feasibility, and effectiveness for treating stroke. It is becoming increasingly clear that the mechanism of action by which multipotent adult stem cells address the complex pathophysiology of stroke is not predominantly their ability to differentiate into cell types that replace tissues lost to injury, but occurs through factors secreted by these cells which promote survival and repair. The paracrine effects of mesenchymal stem cells (MSC) in particular include anti-apoptosis, angiogenesis, protection from glutamate excitotoxic and ischemic insults, neurogenesis, and synaptogenesis. Preclinical studies in animal models of ischemic stroke demonstrate the robust effect of MSC, leading to reduced infarct dimensions and enhanced functional recovery. Recognition of the critical function of MSC paracrine factors has prompted investigation in many different disease models of conditioned medium (CM) obtained from culturing MSC. Seminal studies in rodent stroke models have validated the therapeutic potential of adipose stem/stromal cell (ASC) as well as MSC-CM, demonstrating a similar effect as with cell delivery. These results have led to the concept of producing clinically compliant MSC-CM for testing in human trials. The regulatory pathway for gaining approval to commence clinical testing will require implementation of robust manufacturing processes and quality control systems to develop reproducible final products. In addition, selection of reagents and materials with low risks for introducing toxic substances or adventitious agents is mandatory. Fortunately, clear guidelines exist for developing a suitable manufacturing process, although these guidelines were developed for manufacturing therapeutic cell types and do not pertain in every circumstance to a complex mixture composed of their secretions. An example of a program developing an investigational drug based on MSC-CM and strategies for mitigating risks of encountering regulatory pitfalls is presented.

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Authors and Affiliations

  1. NeuroFx, Inc., 11650 Lantern Road, 46038, Fishers, IN, USA

    Brian H. Johnstone PhD

  2. Indiana Center for Vascular Biology and Medicine, Indianapolis, USA

    Keith L. March MD PhD

  3. Vascular and Cardiac Center for Adult Stem Cell Therapy, Indiana University, Indianapolis, IN, USA

    Keith L. March MD PhD

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  1. Brian H. Johnstone PhD
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Correspondence to Brian H. Johnstone PhD .

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  1. Department of Neurology, Georgia Regents University, Augusta, Georgia, USA

    David C. Hess

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Johnstone, B., March, K. (2015). A Stem-Cell-Derived Cell-Free Therapy for Stroke: Moving Conditioned Medium into Clinical Trial. In: Hess, D. (eds) Cell Therapy for Brain Injury. Springer, Cham. https://doi.org/10.1007/978-3-319-15063-5_14

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