Human Neural Stem Cell Therapy for Chronic Ischemic Stroke
Charting Progress from Laboratory to Patients
Chronic disability after stroke represents a major unmet neurologic need. ReNeuron's development of a human neural stem cell (hNSC) therapy for chronic disability after stroke is progressing through early clinical studies. A Phase I trial has recently been published, showing no safety concerns and some promising signs of efficacy. A single-arm Phase II multicenter trial in patients with stable upper-limb paresis has recently completed recruitment. The hNSCs administrated are from a manufactured, conditionally immortalized hNSC line (ReNeuron's CTX0E03 or CTX), generated with c-mycERTAM technology. This technology has enabled CTX to be manufactured at large scale under cGMP conditions, ensuring sufficient supply to meets the demands of research, clinical development, and, eventually, the market. CTX has key pro-angiogenic, pro-neurogenic, and immunomodulatory characteristics that are mechanistically important in functional recovery poststroke. This review covers the progress of CTX cell therapy from its laboratory origins to the clinic, concluding with a look into the late stage clinical future.
Stem cells and stroke
The past decade has seen a rise in the number of stem cell-derived therapies targeting ischemic stroke in preclinical and early clinical studies. Corroborated by numerous scientific reports, the therapeutic benefits of stem cells include an extension of the time window for drug intervention, improvement of neurological deficits, reduction of infarct volume, pro-regenerative cerebral reorganization, mitigation of poststroke neuro-inflammation, and tissue restoration, all of which depend on the time after infarct, cell type used, and route of administration1–3. The wide range of effects observed for stem cell therapies demonstrates that functional recovery after stroke occurs via multiple mechanisms rather than a single target4–6. Research indicates that the mode of action may depend on the stem cell type and other key factors, including infarct size and location, mode of intervention, and timing poststroke6–8. Thus, some understanding of the cellular, molecular, and biochemical events that are involved in the mode of action of a stem cell type is a prerequisite to improving and optimizing its therapeutic benefits.
Our 2012 review of cell therapy in stroke showed the wide variety of cell types used preclinically and clinically in stroke treatment research1. Mesenchymal stromal cells (MSCs) of multiple origins and phenotypes are most commonly employed in the literature and mainly applied systemically in high doses in acute stroke settings, because of their nonengraftment and potent “drug-like” biological activity. Neural stem cells (NSCs), by contrast, are multipotent cells that are derived from developing or adult brain tissue or differentiated from pluripotent cells such as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in culture. These stem cells have both capacity for engraftment and neural cell differentiation as well as potent biological activity and are delivered intracerebrally in smaller volumes and cell doses; we believe that they are more suitable in patients presenting with pre-existing chronic, stable disability. Currently, there is a growing number of hNSC-derived therapies in preclinical development for ischemic stroke (Table). Leading these therapies, ReNeuron's CTX0E03 cell line (CTX) has been evaluated in a first-in-human, single-center trial in patients with moderate-to-severe disability, 6 months to 5 years after ischemic stroke9. Currently, a Phase II stroke trial in patients with upper-limb disability, 3–12 months poststroke is underway across multiple sites in the United Kingdom (clinicaltrials.gov NCT02117635). In this review, we summarize nearly 15 years of research behind the CTX line and discuss its mode of action together with implications for therapeutic potential in stroke disability.