Regenerative neurology: meeting the need of patients with disability after stroke

If regenerative neurology restores function, it will meet a huge unmet need and change dogma

Treatment of stroke in the acute phase has come a long way with the development of paramedic, emergency department and stroke team pathways for hyperacute assessment and management with intravenous thrombolysis, endovascular clot retrieval and hemicraniectomy. Acute stroke units reduce mortality and morbidity by up to 20% or more.1 An estimated 80% of stroke patients survive for one year after stroke, with the large majority being left with chronic disability.2 In Australia and many other countries around the world, stroke is the leading cause of adult disability.3 It is estimated that up to 450 000 Australians have disability after stroke.4,5

The only intervention currently available to stroke survivors is rehabilitation. Increasing evidence suggests that rehabilitation complements the natural functional recovery process that can often continue for months or years after stroke.6 However, there are persisting gaps in our understanding of the basic biological pathways that drive post-stroke recovery, and these pose challenges in applying evidence-based rehabilitation strategies in the real world. This becomes especially critical as patients often need a combination of rehabilitation strategies that cater for their specific disability and complement their potential for long-term recovery. These are often required beyond the period for which rehabilitation services are currently made available due to resource constraints.7 So where does that leave us in 2017?

Regenerative neurology or stem cell therapy may provide an answer to this unmet need by potentially restoring neurological function in an individualised manner. Many stem cell researchers and clinicians hold the view that the field of regenerative medicine may have as large an impact on humanity as antibiotics.8

Basics of stem cells

Stem cells are unique in possessing two qualities — the capacity for self-renewal and the potential for multilineage differentiation. If a stem cell is pluripotent, it can give rise to cells derived from all three germ layers (ectoderm, mesoderm and endoderm) that differentiate into different tissues during embryonic development. On the other hand, a multipotent stem cell tends to generate limited cell types, often relevant to the organ from which the stem cell was derived — for example, haematopoietic stem cells (HSCs) tend to generate blood and immune cell types. Embryonic stem cells isolated from the very early embryo are pluripotent while adult somatic stem cells derived from adult organs, such as mesenchymal stem cells from bone marrow, are multipotent, similar to HSCs.

A significant clinical limitation to the use of embryonic stem cells therapeutically is the potential for them to form tumours, such as teratomas which have multiple cell types from the different embryonic lineages (hair, bone, teeth, heart muscle, etc).9 In contrast, to date, multipotent cells such as mesenchymal stem cells are considered safer, with animal studies reporting no increase in tumorigenicity.10

In 2006, Yamanaka (2012 Physiology or Medicine Nobel Laureate) showed that somatic cells (skin fibroblasts) could be engineered genetically by four genes (known as the Yamanaka factors) to produce pluripotent cells similar to embryonic stem cells.11 This third type of stem cell is termed an induced pluripotent stem cell (iPSC). This discovery has radically transformed stem cell research and proffers the concept of personalised regenerative medicine. Early clinical trials have already started deriving iPSCs from an individual’s fibroblasts for autologous (self-)treatment or personalised medicine.12 The findings of preclinical studies in stroke models have provided encouraging evidence for potential for neuroregeneration and useful insights into potential applicability in the future.13-15

Chronic stroke and local injection

Last year was an exciting one for stem cell therapy in stroke patients. There were two high impact publications documenting early phase clinical studies with two different multipotent stem cells, SB623 and CTX0E03. Both are genetically modified stem cell types, one isolated from fetal brain tissue16 and the other from adult bone marrow.17 Two independent research teams from reputable institutions in the United Kingdom and United States performed these studies with industry funding (ReNeuron and San Bio, respectively).

This research examined two key questions in relation to study design:

• Is it potentially useful to treat stroke survivors in the chronic phase when their disability has plateaued, sometimes as long as 3 to 4 years after stroke?

• Is intracerebral implantation of stem cells a feasible route of administration?

Published preclinical and preliminary clinical data indicate that the design of the studies was valid, although research opinion is often divided as to optimum timing and route of administration of cell transplantation.9

Why was stem cell therapy not administered in the acute phase after stroke in these studies? There may be a number of clinically pragmatic answers to this question — in the acute phase, patients may be too medically unstable to undergo neurosurgery. Moreover, patients are often still showing rapid improvement, so it would be problematic to measure any benefit above that of optimum acute stroke unit care, when disability has not yet plateaued.18

Why was a neurosurgical implantation chosen? “Functional neurosurgery” is a fast-developing specialty and these neurosurgeons routinely implant electrodes for deep brain stimulation to treat Parkinson disease. Thus they have the expertise to inject, via a narrow bore cannula, deposits of stem cells into multiple sites within the human brain. One benefit to the patient of intracerebral implantation is that the cells remain within the brain and can be imaged non-invasively.19 An alternative route of administration used in earlier clinical studies was intravenous injection.20 Initially, this approach was considered safer than intracerebral implantation, but it is now appreciated that there is a theoretical risk of distant tumorigenicity, in that stem cells injected intravenously may deposit widely throughout a number of organs within the body (ie, lung, liver, etc.) and may interact with presymptomatic tumours.20

Is it safe?

Early phase clinical trials characteristically involve small numbers of patients to minimise the number at risk if there is a serious treatment-related adverse event. In the two studies described above,16,17 27 patients were followed for 12 months after treatment, which is a generally accepted timeframe. The studies stated that no adverse event directly attributable to the stem cell therapy was found. However, the neurosurgical procedure of creating a burr hole and entering the brain to administer the cells did result in appreciable anticipated adverse events (ie, haematoma, headache and other symptoms related to the consequent reduction of intracranial pressure). It is noteworthy that both studies will continue surveillance of all patients after 12 months to detect any longer term adverse events.

We propose an alternate perspective with respect to the claims that no stem cell-related adverse events occurred. Stem cells implanted into the brain are known from preclinical data to differentiate into neural cells and probably integrate within the brain.9 In theory, this cellular behaviour has the potential to form an epileptogenic focus. A small number of patients in each of the two high impact studies16,17 were reported to have seizures. With this limited clinical dataset it cannot be concluded whether their seizures arose from the neurosurgical procedure, as suggested in the publications,16,17 or was related to the stem cells. We propose that larger phase 2/3 studies should incorporate electroencephalography investigations to better understand the association of seizures with intracerebral implantation stem cell therapy.

The clinical data in these two early phase clinical studies supports the clinical feasibility and safety of intracerebral implantation of stem cells in patients with chronic disability after stroke. Both studies used an escalating dose of stem cell therapy. Cell doses of up to 10 million SB623 and 20 million CTX0E03 stem cells may be used for future larger phase 2 studies.

So: does it work?

This question will not be answered with any degree of certainty for a number of years as we await the results from large, multicentre, multinational, double-blind, randomised controlled clinical trials. While preclinical data from animal studies suggest an overall functional improvement of 40.6%, the extrapolation of these findings to human stroke pathophysiology is limited by: (i) species-specific differences; and (ii) the fact that controlled induction of cerebral ischaemic lesions in animals is not fully representative of the heterogeneous lesion load seen with human stroke.9

Early clinical studies enrolled a heterogeneous mix of patient groups. Most of these studies were open label and single arm and thus not designed to answer the question of efficacy. Therefore, at present, it is difficult to postulate any differential benefit for specific patient or stroke subgroups.18 From a mechanistic perspective, there are a number of theories from preclinical data on how stem cell therapy may decrease post-stroke disability (Box), with neuroplasticity considered to be an important factor.21

An aspect of immense practical relevance is that standardised rehabilitation was not provided to participants in these studies. There is an ongoing debate about the potential confounding effect of rehabilitation on functional and structural outcomes. However, rehabilitation is accepted as a standard of care to optimise natural recovery, and guidelines for stem cell research such as Stem Cell Therapy as an Emerging Paradigm for Stroke (STEPS)22 recommend its inclusion in trial design. Stroke clinicians will know from everyday experience that significant improvement in neurological function many years after an ischaemic stroke is rarely observed. The two studies described above16,17 are very important in the field of regenerative neurology in that both found an associated improvement in function in the chronic phase of stroke among patients with different areas of stroke-induced injury. In light of the emerging evidence for long-term potential to relearn that can be harnessed by rehabilitation, stem cell implantation along with targeted and protracted rehabilitation could have a synergistic and biologically plausible impact on post-stroke recovery.

It is of fundamental interest that both studies described changes on magnetic resonance imaging (MRI) of the human brain after treatment. It was suggested that these MRI findings may not be explained by the neurosurgical procedure alone.17 These preliminary findings may present an opportunity for reverse translational research, from the clinic back into the research laboratory, to gain a better understanding of how changes in the human brain may occur after stem cell therapy.

At this juncture of stem cell research in stroke, there are three important points to be considered:

• The preclinical and early clinical data which suggest that stem cell therapy may be helpful are becoming encouragingly robust.23

• The preponderance of failed translation efforts from preclinical to clinical therapeutics in stroke highlights that continued exercise of scientific rigor is critical.

• Ongoing stem cell tourism across the world and in Australia to reach centres that operate for financial gain without regard to research integrity or patient safety poses a significant danger to the credibility of this field.24

The current regulatory framework in Australia for oversight of cellular therapies has significant gaps in scope as well as implementation. It is a matter of urgency that our politicians and regulatory authorities collaborate with their counterparts in the US, European Union, Japan and other regions where innovative approaches are being implemented to develop the field while creating adequate safeguards to protect patient interests.25,26

Exciting scientific research is that in which the questions raised outweigh the answers. We suggest the quest to fulfil the unmet need for treating disability after stroke has taken a step forward.

Box – Putative mechanisms of action of stem cells in stroke*

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* Adapted with permission from Nagpal et al.21