Ischaemic stroke remains a leading cause of death and disability. Current stroke treatment options aim to minimise the damage from a pending stroke during the acute stroke period using intravenous thrombolytics and endovascular thrombectomy; however, there are no currently approved treatment options for reversing neurological damage once a stroke is completed. Preclinical studies suggest that cell therapy may be safe and effective in improving functional outcomes. Several recent clinical trials have reported safety and some improvement in outcomes following cell therapy administration in ischaemic stroke, which are reviewed. Cell therapy may provide a promising new treatment for stroke reducing stroke-related disability. Further investigation is needed to determine specific effects of cell therapy and to optimise cell delivery methods, cell dosing, type of cells used, timing of delivery, infarct size and location of infarct that are likely to benefit from cell therapy.
Until recently, intravenous recombinant tissue plasminogen activator was the only proven effective treatment for acute stroke. Endovascular thrombectomy has now been added to our arsenal for acute stroke treatment following the publication of five randomised trials demonstrating highly significant treatment effects favouring endovascular therapy.1–6 Outcome data support advancements in acute stroke care and neurorehabilitation with a significant increase in stroke survivors over time.7 However, despite these advancements, stroke remains a leading cause of long-term disability.8 For patients with residual deficits after stroke, we have no currently approved therapy for restoring function.
Cell therapy is one approach to enhancing recovery after stroke. In animal models, delivery of several different types of stem cells reduce infarct size and improve functional outcomes.9 Clinical trials of cell therapy completed in the 2000s mostly treating small cohorts of patients with chronic stroke demonstrated adequate safety and a suggestion of efficacy with the use of cell therapy. Kondziolka and colleagues used N-Tera 2 cells derived from a lung metastasis of a human testicular germ cell tumour that when treated with retinoic acid generate postmitotic neurons that maintain a fetal neuronal phenotype indefinitely in vitro (LBS neurons). LBS neurons were stereotactically implanted around the stroke bed of chronic subcortical ischaemic stroke. This study demonstrated safety and feasibility of stereotactic cell implantation, although there was no significant improvement in functional outcomes.10 11 Using a similar stereotactic approach implanting cells into the basal ganglia, Savitz and colleagues transplanted LGE cells (fetal porcine striatum-derived cells, Genvec) in five patients. Two patients showed improvements, but two patients experienced adverse effects including delayed worsening of neurological symptoms and seizure resulting in early termination of the study.12 Bang and colleagues reported the safety and feasibility of intravenous infusion of autologous mesenchymal stem cells (MSCs) with no reported adverse effects in five patients treated with intravenous MSCs. Although they reported some initial motor improvements, at 12 months, there was no significant difference in motor scores.13 These early clinical trials mostly focused on chronic subcortical strokes, but more recent trials are now investigating cell therapy for treatment of both cortical and subcortical infarcts. This review discusses the considerations for design of cell therapy trials and summarises the results of more recent studies.
|Clinical trial/sponsor||Age||Time after stroke||Additional selection criteria||Cell type||Route||Stroke location||Patients (n)||Safety results||Efficacy results|
|MASTERS/Athersys||18–83||24–48 hours||NIHSS 8–20, infarct 5-100cc, premorbid mRS 0–1||Multistem adult-derived stem cell product||Intravenous||Cortical||129||Similar SAE at 1 year 22(34%) versus 24 (39%) placebo,
Lower mortality—5 deaths (8%) versus 9deaths (15%) in placebo19
|No effect on 90-day Global Stroke Recovery Assessment (mRS 0–2, NIHSS increase by 75%, Barthel Index >95) but trend towards improved outcome with earlier delivery of cells19|
|InveST/Department of Biotechnology, India||18–75||7–29 days||NIHSS >7, GCS >8, BI <50, paretic arm or leg stable >48 hours||Autologous marrow-derived stem cells||Intravenous||120
(58 cell therapy)
|61 AE (33%) and eight deaths versus 60 AEs (36%) and five deaths placebo22||No effect on 180-day Barthel Index Score, mRS shift or score >3, NIHSS, change of infarct volume22|
|RECOVER-Stroke/Aldagen||30–75||13–19 days||NIHSS 7–22, mRS >3||ALDHbrautologous marrow-derived stem cells||Intracarotid infusion distal to ophthalmic||Anterior circulation ± subcortical||29 IA, 19 sham||12 SAE IA, 11 SAE sham; 0 cell-related SAE23||No difference in mRS, Barthel, NIHSS at 90 days or 1 year|
|PISCES-II/ReNeuron||40–89||2–13 months||Paretic arm with NIHSS motor arm score 2–3||CTX0E03 DP allogeneic human fetal neural stem cells||Stereotaxic infusion into ipsilateral putamen||21||Pending||Pending|
|Sanbio||18–75||6–60 months||NIHSS>7, mRS 3–4, stable symptoms>3 weeks||SB623 allogeneic marrow-derived stem cells transiently transfected with plasmid encoding Notch122||Stereotaxic infusion peri-infarct||Subcortical ± cortical component24||18||28 SAE, 0 cell-related SAE25||Improved ESS at 6 months (p<0.01) and 12 months (p<0.001)
Improved NIHSS at 6 months (p<0.01) and 12 months(p<0.001)
Improved Fugl-Meyer at 6 months (p<0.001) and 12 months(p<0.001)25
|PISCES/ReNeuron||>60, male only||6–60 months||Persistent hemiparesis, Stable NIHSS over 4 weeks (Pt 2||CTX0E03 DP allogeneic human neural stem cells||Stereotaxic infusion into putamen||Subcortical||11||16 SAE (in nine patients), 0 cell-related SAE28||Improved NIHSS at 2 years (p=0.002), No change, Barthel Index, MMSE, Ashworth, mRS28 29|
AE, Adverse Event; ARAT, Action Research Arm Test; BI, Barthel Index; DP, drug product; ESS, European Stroke Scale; IA, intra-arterially; MASTERS, Multistem Administration for Stroke Treatment and Enhanced Recovery Study; MMSE, Mini-Mental Status Examination; mRS, modified Rankin Score; NIHSS, National Institutes of Health Stroke Scale; PISCES, Pilot Investigation of Stem Cells in Stroke; SAE, Serious aAverse Events.