EPO: Erythropoietin; G-CSF: Granulocyte-Colony Stimulating Factor; MSC: Mesenchymal Stem/Stromal Cell; RCT: Randomized Controlled Trial; UCB: Umbilical Cord Blood

Stem cell therapy for the treatment of cerebral palsy is a rapidly expanding area of research that has been identified as a high priority by consumers [1]. There are several types and sources of stem cell therapies under investigation. Stem cell treatments proposed for cerebral palsy are believed to provide benefit via some or all of the following mechanisms including immunomodulation, paracrine signaling and supporting endogenous reparative processes [2,3]. Importantly, only a sub-set of stem cell types (e.g., neural stem cells) are potentially capable of directly regenerating the brain [3]. In our 2020 systematic review of cerebral palsy intervention evidence, we reviewed four categories of cell therapy interventions: umbilical cord blood (UCB), mesenchymal stem/stromal cells (MSCs), neural-like cells and mobilized peripheral blood and bone marrow mononuclear cells [4].

Since 2004, at least 2,427 people with cerebral palsy have received various stem cell therapies in clinical studies [5]. Examples include phase II studies in Umbilical Cord Blood for children and young adults with cerebral palsy that confer gains in gross motor function [6]. In the last five years, data from several controlled clinical trials has been published, contributing to an increased understanding of the safety and potential efficacy of various stem cell treatments. We now have data to support that some stem cells are safe and may provide gains in motor function greater than those seen with rehabilitation alone [4,6], yet despite this, there are no currently approved cell treatments for cerebral palsy. The purpose of this commentary is to provide a research update on the four cell interventions appraised in our 2020 systematic review [4] and discuss considerations and future research directions for the field.

What is new?

• Over 2400 children with cerebral palsy have received a stem cell therapy in a clinical trial.
• Newer additional clinical trials confirm the effectiveness of Umbilical Cord Blood for cerebral palsy, indicating higher doses are more effective and concomitant erythropoietin increases efficacy.
• Mesenchymal stem cells seem less effective than Umbilical Cord Blood in the chronic injury phase.

UCB was the first cell therapy to be administered for cerebral palsy more than 15 years ago (as documented by Sun 2010) [7]. It is therefore not surprising that UCB was the only cell type to receive a “green light” (“go” since effectiveness established) recommendation in the 2020 traffic light publication [4], with moderate quality evidence to indicate that this treatment is safe and can provide small but significant improvements in gross motor function in children with cerebral palsy. Notably, a recent review of the research landscape identified more than 700 people with cerebral palsy who have been treated with UCB in published and unpublished clinical studies including case reports/series, single-arm and controlled trials [5]. This review also highlighted many individuals who have received UCB via Expanded Access programs in the USA and Europe, under an off-label compassionate access indication. These programs currently offer an alternate access pathway for receiving treatment outside of clinical trials and are becoming increasingly popular [8].

Since the 2020 traffic light publication, new study data from two randomized controlled trials (RCTs) has been published [3,9], adding strength to the “green light” recommendation. Further to their 2013 study, Min et al., 2020 demonstrated that treatment with UCB or erythropoietin (EPO) resulted in a significant improvement in gross motor function, with co-administration of UCB and EPO having a synergistic effect [9]. In addition, results from the ACCeNT-CP trial (NCT03473301) from the Kurtzberg group were recently presented at a conference [10]. Findings suggest that treatment with high dose UCB (10x10⁷/kg) is associated with clinically significant improvements in gross motor function in young children with cerebral palsy. Further to these new published studies, there are currently several active controlled (Phase 2) studies that we expect will be published in the next few years. These include a study comparing autologous UCB to a patient’s own bone marrow cells (NCT01988584) as well as two studies from Russia that use allogeneic UCB (NCT03826498 and NCT04098029).

Interestingly, the field has seen a trend towards more studies utilizing donor (allogeneic) cord blood compared to autologous (a patient’s own) cord blood. Use of allogenic units can overcome the difficulty of feasibly recruiting participants. This is because there is no pre-birth test for cerebral palsy, meaning most people with cerebral palsy do not have autologous units banked. Pleasingly, a recent review of the safety of donor UCB for neurological conditions demonstrated no safety concerns of allogeneic UCB administered to 361 individuals, other than manageable infusion reactions [11]. This safety finding should give confidence to researchers and clinicians about the application of donor UCB for the treatment of cerebral palsy.

The next logical and obligatory step for UCB for cerebral palsy is a Phase 3 trial. This is necessary to provide the required efficacy evidence for regulatory approval. In addition, future research should evaluate the cumulative effect of repeat dosing, and elucidation of optimal cell dosage and timing of treatment using high quality, well-designed studies.

MSC research is an area of great interest in neurological and inflammatory conditions. Whilst evidence is growing, MSCs received a “yellow light” (promising evidence), weak positive recommendation based on moderate quality evidence for improving gross motor function in cerebral palsy. Recently, we highlighted the mounting clinical data of MSCs for cerebral palsy [5], identifying six published Phase 2 trials including one new Phase 2 RCT published [12] as well as lower-level evidence that was not included in our previous systematic review [4]. We are also awaiting results from a completed Phase 3 trial (NCT01929434), which may hold potential for enabling regulatory approval of MSCs for cerebral palsy.

The yellow light recommendation for MSCs reflects the complexity of the cell therapy field, with certain MSC lines being tested for efficacy in large-scale clinical trials (Phase 3) yet others still being validated for safety in Phase 1. MSCs require manufacturing, which can result in different cell yields and potency between interventions. There are growing concerns over the lack of standardization across cell products and expansion [13-15], which will affect manufacturing scale-up and regulatory approval, plus the validity of data aggregation across different MSC formulations. Other sources of heterogeneity in MSC research include dose and route of administration, as well as participants treated. For instance, some patients have been treated with hundreds-of-millions of cells with still no indication of optimal dosing requirements for efficacy [16]. Additionally, intravenous and/or intrathecal, subcutaneous and intramuscular administration routes have been used in clinical trials recruiting children and adults of various ages. Sources of MSCs used in clinical trial also remain varied, with MSCs derived from allogeneic and autologous bone marrow, allogeneic cord tissue and allogeneic UCB advancing through clinical trials. Scalability and feasibility of a number of these sources remain a concern. Extensive optimization is still required.

So far, we have only seen one head-to-head study comparing allogeneic UCB versus repeat dose allogeneic cord tissue MSCs (ACCeNT-CP, Duke University: NCT03473301). Whilst full study results are yet to be published in a peer-reviewed journal, early results from a poster abstract indicate that UCB, not MSC treatment, was associated with improved gross motor outcomes at 12 months [10]. There may well be one cell type that is superior to others for particular groups of individuals with cerebral palsy. Nevertheless, MSCs have demonstrated safety and early efficacy for cerebral palsy [16]. It is likely that very early timing of administration is important, because MSCs have a strong immunomodulatory mechanism with a short cell persistence. It follows that there are several trials showing promise for MSCs as an early treatment for acute brain injuries (e.g., hypoxic-ischemic encephalopathy; stroke) [17,18].

Future MSC work will need to focus on continued standardization of cell product as different sources of MSC progress through the research pipeline. The field also needs to be informed by optimized cell dosing using appropriate administration routes. Additionally, we encourage more head-to-head clinical trials of MSCs with different cell types to determine the most efficacious cell therapy for cerebral palsy.

Three controlled trials (two RCTs and one non-randomized) of neural and neural-like stem cells including olfactory ensheathing cells, neural stem cells and neural progenitor cells were appraised in the traffic light publication [4], resulting in a weak positive “yellow light” recommendation based on low quality evidence. Since then, there have been no new studies published using neural or neural-like stem cells for cerebral palsy. Moreover, we are not aware of any active trials listed on clinicaltrials.gov using these cells.

Treatment with “neural stem cells” for cerebral palsy is associated with a number of additional challenges compared to other cell therapies. Neural stem cells are the only cell type proposed for cerebral palsy that are truly regenerative. However, to be efficacious, cells must engraft, survive long term and differentiate. Application of neural stem cells thus requires invasive neurosurgical placement into the brain coupled with use of long-term (possibly even life-long) immunosuppression to sustain engraftment. Although these required neurosurgical procedures and medications are commonly used for other indications, the associated risks are not insignificant. In addition, neural stem cells are often derived from ethically complicated sources (e.g., fetal tissue), adding to the complexity of this cell intervention.

Despite these challenges, significant research progress is being made applying neural and neural-like stem cells for the treatment of other neurological conditions including stroke [19], NCT03629275), Amyotrophic Lateral Sclerosis [20], Pelizaeus–Merzbacher disease [21] and neuronal ceroid lipofuscinosis [22]. Emerging data continues to provide hope that neural stem cells could be useful for the treatment of cerebral palsy. Encouragingly, community support for this type of complex stem cell treatment has been recently confirmed [23]. Additional research investigating the acceptability of neural and neural-like stem cell treatment more specifically within the cerebral palsy community may facilitate future trials using these cell types.

Mobilized peripheral/bone marrow cell therapy is typically an autologous intervention that involves pre-treatment with granulocyte-colony stimulating factor (G-CSF) to induce cellular proliferation and release of white blood cells from the bone marrow before cells are collected then reinfused [24,25]. Both mobilized peripheral blood and bone marrow cell therapy are proposed to have similar mechanisms of action to UCB, however, these cells are less potent and do not have equivalent differentiation potential [3].

Three RCTs have been conducted that assess mobilized peripheral or bone marrow cells for cerebral palsy, with this intervention receiving a “yellow light”, weak positive recommendation for improving gross motor function [4]. Since publication of the traffic light paper, there has been no new published research aside from case reports. The majority of evidence remains in the early phases of research with 10 Phase 1 studies and six case series or reports [5]. Although the data is limited, Phase 2 studies have indicated two key points. Firstly, that bone marrow mononuclear cell treatment is not as effective as MSCs in improving gross motor function [26], demonstrating that bone marrow may not be the most efficacious therapy available. We now also await publication of results from a trial that compares autologous banked UCB with autologous bone marrow stem cell treatment for cerebral palsy (ACT for CP: NCT01988584) that might elucidate most effective treatments. Early trial results have been submitted to clinicaltrials.gov but are yet to be made public. Secondly, that the use of G-CSF treatment alone without collection and reinfusion of peripheral blood cells, may be beneficial in-itself [25]. If G-CSF does provide benefit as a standalone treatment, this could be confounding findings from those treated with autologous peripheral blood and warrants further investigation.

Unlike some other stem cell treatments, bone marrow/peripheral blood cells are an autologous cell source that is readily available for most, if not all, children with cerebral palsy. For some families, bone marrow therapy is seen as a pragmatic autologous cell therapy, when autologous UCB is not available.

Autologous cell therapies may also be perceived as lower risk than donor treatments and have therefore been exploited as a popular treatment by private clinics [27]. It is important to recognize that bone marrow mononuclear cell treatments are highly invasive, often requiring painful bone marrow harvesting. Not to mention, intrathecal re-administration is often used for both bone marrow and peripheral blood treatment and carries known risks and discomfort [28,29]. These should be important considerations when determining if treatment is appropriate and necessary, particularly when benefit remains unclear. For children with cerebral palsy, the harvesting and infusion procedure may lead to procedural anxiety and/or enlarge their chronic pain burden which could be detrimental to development.

Heterogeneity

There is no ‘typical patient’ with cerebral palsy. Cerebral palsy is a heterogenous condition, with multiple causal pathways, numerous sub-types and severities, further personalized by the presence of multiple comorbidities such as epilepsy and intellectual disability. Not only does this mean there is large variation in the cerebral palsy population’s response to treatments broadly, but for stem cell therapies there will be variations in the population regarding available biological targets for treatment. For example, children with a hypoxic pathway to cerebral palsy resulting in a prolonged inflammatory load may respond differently to children with a genetic causal pathway.

The current stem cell evidence base for cerebral palsy is confounded by trials that include all motor sub-types, severities, causal pathways and ages. Plus, studies have used a range of different stem cell types, with varying formulations, dosage, number of doses, route of administration, and timings post brain injury. Future research should focus on recruiting homogenous sub-types of participants using strict inclusion criteria or should recruit large samples with sufficient statistical power to account for population variations amongst sub-groups. In addition, there needs to be harmonization across studies. If research optimization were to be broadly implemented, it would be possible to more accurately aggregate data and compare cells head-to-head, to accelerate knowledge gains towards the discovery of novel treatments. As an interim step, individual participant data meta-analyses may elucidate best responders and assist with calculating effect sizes so that future clinical trials can be designed with precision, meaning larger effect sizes with smaller sample sizes at lower cost and in shorter time frames. Precise trials with more definitive findings will accelerate the pathway to regulatory approval of efficacious therapies. Future trials should also consider immediate and long-term follow-up timepoints, since the current studies use a variety of endpoints (3-, 6-, and 12-month follow-ups). Little is known from clinical trials about when the anti-inflammatory benefits wear off in order to select optimal repeat dose intervals, even though it is biologically plausible the interval is short (from days to 3-months). Plus, there is no data to guide whether repeat treatments provide a cumulative long-term benefit. Co-design of future trials within translational networks that include consumers, scientists, clinician-scientists and commercial partners will accelerate the development of feasible and affordable products with viable manufacturing scale-up, that produce clinically meaningful outcomes to families (such as motor, cognition, communication, sleep and/or pain management).

Commercialization

A commercialization market shift is occurring within mainstream healthcare, and this will have implications for stem cell therapies. For example, cord blood banks are being bought out and amalgamated by large commercial entities reducing competition, plus universities and companies are now filing patents not only for novel cell products but also for dosing protocols to position themselves as market leaders and exclusive commercial operators. These commercial dynamics will affect the type and scope of regulatory approvals that are possible and consequently the price points for governments or insurers wanting to purchase approved therapies for citizens and policyholders. Advanced and clear regulatory pathways exist for pharmacological agents, but the regulatory pathways for cell therapies are still in their infancy, and paying attention to the shifting commercialization landscape will be necessary in addition to the scrutiny of good science.

Stem cells provide a promising, emergent therapy option for children with cerebral palsy. It is conceivable that within five years, regulatory approval will be realized for UCB therapy. With the trend towards preferentially using more feasible allogenic UCB units, there is likely to be high consumer demand given that many children with cerebral palsy will be eligible and supported by their astute and consenting parents. It is important that clinicians and healthcare systems develop readiness for adoption. More high-quality clinical trial research is warranted using optimized and harmonized protocols, with a priori planning for head-to-head comparisons between cell types, doses and patient sub-groups, with a view to also exploring whether combination therapies augment clinical gains. To achieve progress in a timely manner, collaboration between consumers and stakeholders at all stages of the research pipeline will be essential.

No specific funding to declare.

None to declare.