Dr. Lawrence Wechsler

Dr. Lawrence Wechsler

A conversation with Dr. Lawrence Wechsler, MD, Henry B. Higman Professor and Chair, Department of Neurology, University of Pittsburgh Medical School, about the role of cell therapy in chronic stroke.

Interviewed by Deepak Gulati, MD, Assistant Professor of Neurology, Ohio State University.

They will be discussing the paper “Cell Therapy for Chronic Stroke,” published in the May issue of Stroke. The article is part of a Focused Update in Cerebrovascular Disease centered on stem cells and cell-based therapies.

Dr. Gulati: Can you please summarize in simple words the mechanism of action of stem cell therapy in chronic stroke? Also, what are your thoughts on the modes of administration?

Dr. Wechsler: In chronic stroke, the most likely mechanism is paracrine release of growth factors and cytokines that act locally to promote functional recovery. These factors increase neurogenesis, synaptogenesis, angiogenesis and reduce inflammation. It is not known which of these processes is most important, and the pleomorphic effects of cell therapy make cell therapy an attractive approach in chronic stroke. Stereotactic implantation of cells in chronic stroke is most likely to be beneficial to assure delivery of cells to the area of injury in this late stage at a time when disruption of the BBB or homing signals are not operative to allow cells to reach the infarct area by other modes of delivery.

Dr. Gulati: Do you think more animal studies are needed to refine our understanding on this topic?

Dr. Wechsler: Considerable information may be gained by additional animal studies including a greater understanding of mechanisms. Animal studies inform clinical trials, and observations from clinical trials raise issues that can be addressed with further animal studies. Both are necessary.

Dr. Gulati: What are your thoughts on the ongoing trial ACTIsSIMA and the PISCES 3 trial (not started yet), especially when both are using a stereotactic surgical approach? Is there any role or need of trials with other modes of delivery in chronic stroke?

Dr. Wechsler: We are anxiously awaiting the results of the now completed ACTIsSIMA trial, which included a double blinded placebo group. The promising results of previous unblinded studies may have been biased by placebo effect. PISCES 3 uses a similar double blind approach with stereotactic implantation of cells in chronic stroke but with a different cell type from ACTIsSIMA. Both studies will greatly advance our understanding of cell therapy for chronic stroke.

Dr. Gulati: Could you please summarize the major challenges with stem cell research, especially in the setting of chronic stroke, or the next critical research questions to be addressed regarding use of stem cell in stroke?

Dr. Wechsler: There remain many important variables to be explored. What are the limits of any plasticity after stroke that can be altered by cell therapy? Where are cells best delivered — in the center of the stroke, surround, putamen? What paracrine factors are most important in enhancing recovery?  Does the stereotactic procedure itself play a role independent of the cells? Are specific cell types more effective than others?

Dr. Gulati: Do you think this topic of stem cell therapy in stroke has gained enough attention to get support from industry or the NIH or other national/international funding agencies?

Dr. Wechsler: Absolutely yes. The impressive results from early Phase II studies should attract the attention of funding agencies. Chronic stroke is a gap in our armamentarium of stroke treatments. There is currently no treatment for millions of stroke survivors with residual deficits and disabilities.

Dr. Gulati: Currently, the trials on chronic stroke are mainly focused on motor improvement. What are your thoughts on the need for trials focused on cognitive linguistic improvement as the endpoint? 

Dr. Wechsler: Motor deficits are disabling and optimal for proof of principle trials because of standard ways of measuring outcomes. However, other outcomes such as cognitive improvement are at least as disabling, and treatments that address such disabilities are needed.

Dr. Gulati: What advice do you have for young investigators interested in pursuing research on stem cell therapy?

Dr. Wechsler: It is a fertile area for productive research. Rehabilitation and recovery is poised to be the next major breakthrough in stroke treatment. As we learn more about cell therapy and stroke recovery, our treatments will continue to improve our ability to help our patients.

Dr. Gulati: What inspired you to go into stem cell research in stroke?

Dr. Wechsler: Stroke recovery is an unmet need. The patients suffering with disability months and years after stroke are the motivation to continue this work.

Dr. Gulati: Thank you for taking time out from your busy schedule for this interview. It was interesting to learn from you about cell therapy in chronic stroke as being one of the fertile areas for productive research and how it could help a large number of stroke patients. It appears that there are still many unanswered questions in this field which potentially lead to hope and opportunities for investigators, clinicians and patients.