Human neural stem cells could meet the clinical problem of critical limb ischemia

Human neural stem cells (hNSCs) promote neovascularization in ischemic mouse model adductor muscle. High-power view shows hNSCs labelled with human specific nestin (green) surrounded by host cells labelled with α-smooth muscle actin (red) counterstained with Hoechst (blue). ReNeuron

Press release issued: 25 November 2013

New research, led by academics in the University’s School of Clinical Sciences, has shown human neural stem cells could improve blood flow in critical limb ischemia through the growth of new vessels.

The study, led by academics in the University of Bristol’s School of Clinical Sciences, is published online in the American Heart Association journal Arteriosclerosis, Thrombosis, and Vascular Biology.

Current stem cell therapy trials for the treatment of CLI have revitalised new hope for improving symptoms and prolonging life expectancy. However, there are limitations on the use of autologous cell therapy. The patient’s own stem cells are generally invasively harvested from bone marrow or require purification from peripheral blood after cytokine stimulation. Other sources contain so few stem cells that ex vivo expansion through lengthy bespoke Good Manufacturing Practice processes is required. Ultimately, these approaches lead to cells of variable quality and potency that are affected by the patient’s age and disease status and lead to inconsistent therapeutic outcomes.

In order to circumvent the problem a team, led by Professor Paolo Madeddu in the Bristol Heart Institute at the University of Bristol, has used a conditionally immortalised clonal human neural stem cell (hNSC) line to treat animal models with limb ischaemia and superimposed diabetes. The CTX cell line, established by stem cell company ReNeuron, is genetically modified to produce genetically and phenotypically stable cell banks.

Results of the new study have shown that CTX treatment effectively improves the recovery from ischaemia through the promotion of the growth of new vessels. The safety of CTX cell treatment is currently being assessed in disabled patients with stroke [PISCES trial, NCT01151124]. As a result, the same cell product is immediately available for starting dose ranging safety and efficacy studies in CLI patients.

Professor Paolo Madeddu, Chair of Experimental Cardiovascular Medicine and Head of Regenerative Medicine Section in the Bristol Heart Institute at the University of Bristol, said: “Currently, there are no effective drug interventions to treat CLI. The consequences are a very poor quality of life, possible major amputation and a life expectancy of less than one year from diagnosis in 50 per cent of all CLI patients.

“Our findings have shown a remarkable advancement towards more effective treatments for CLI and we have also demonstrated the importance of collaborations between universities and industry that can have a social and medical impact.”

Dr John Sinden, Chief Scientific Officer of ReNeuron, added: “The novel idea of using neural stem cells to treat vascular disease arose from a chance discussion with Professor Madeddu. The discussion led to a short pilot study with our cells producing very clear data, which then developed into a further eight experiments exploring different variants of the disease model, the product formulation and dose variation.

“The study also explored the cascade of molecular events that produced vascular and muscle recovery. It is a great example of industry and academia working successfully towards the key goal, clinical translation.”

Paper: Clinical-grade human neural stem cells promote reparative neovascularization in mouse models of hindlimb ischemia, Rajesh Katare, Paul Stroemer, Caroline Hicks, Lara Stevanato, Sara Patel, Randolph Corteling, Erik Miljan, Indira Vishnubhatla, John Sinden, Paolo Madeddu, Arteriosclerosis, Thrombosis, and Vascular Biology, published online by the American Heart Association, November 7, 2013.

Further information

About the Bristol Heart Institute
The Bristol Heart Institute (BHI), founded in 1995, consists of over 200 researchers and clinicians, located in the University of Bristol and across Bristol NHS Trusts, who are united in the mission to translate basic scientific research into novel clinical practice thereby improving patient outcome and care. It brings together internationally respected experts from many disciplines of cardiovascular science and disease. Indeed, the BHI is now an internationally recognised centre of excellence for performing interdisciplinary cardiovascular research that takes basic science discoveries into the clinic.

As well as improving collaboration between scientists and clinicians within the BHI, and improving medical treatment of cardiovascular diseases, we also aim to communicate our research findings to the public.

About ReNeuron
ReNeuron is a leading, clinical-stage stem cell business. Our primary objective is the development of novel stem cell therapies targeting areas of significant unmet or poorly met medical need.

ReNeuron has used its unique stem cell technologies to develop cell-based therapies for significant disease conditions where the cells can be readily administered “off-the-shelf” to any eligible patient without the need for additional drug treatments. The lead therapeutic candidate is our ReN001 stem cell therapy for the treatment of patients left disabled by the effects of a stroke. This treatment is currently in clinical development. We are also developing stem cell therapies for other conditions such as critical limb ischaemia, a serious and common side effect of diabetes, and blindness-causing diseases of the retina.

We have also developed a range of stem cell lines for non-therapeutic applications –our ReNcell® products for use in academic and commercial research. Our ReNcell®CX and ReNcell®VM neural cell lines are marketed worldwide under license by USA-based Merck Millipore.

ReNeuron is incorporated in and operates primarily in the UK. Our shares are traded solely on the London AIM market under the symbol RENE.L.