Review of Clinical Trials Using Neural Stem Cells
- 0. Both authors are co-first authors
- 1. Laboratoire Neurobiologie and Transgenese, Institut de Biologie en Santé, France
- 2. Laboratoire Neurobiologie and Transgenese, Université d’Angers, France
ABSTRACT
The use of stem cells in clinical trials started several years ago for regenerativebased therapies or for the treatment of tumours. After brain injuries or neurodegenerative diseases, neural stem cells represent a promising strategy to repair the affected tissue and to replace degenerative cells. Neural stem cells can migrate and differentiate into neurons, astrocytes and oligodendrocytes, and thus could serve as promising therapeutic solutions. However, these cells can represent a potential source of cancer stem cells in tumour brain where they are responsible of recurrence, invasiveness and resistance to current treatments. Thus, few clinical trials involving endogenous, genetically modifiedor derived-neural stem cells have been conducted in the world to treat brain disorders. According to the website www.clinicaltrials.gov only 37 clinical trials involving neural stem cells are listed. Most of them use derived-neural stem cells to treat brain disorders (neurodegenerative diseases, injuries or tumours). For the future, a better approach would be to target directly endogenous stem cells.
KEYWORDS
• Brain disorders
• Brain tumours
• Clinical trials
• Neural stem cells
• Neurodegenerative diseases
• Stem cells
CITATION
Barreau K, Lépinoux-Chambaud C, Eyer J (2016) Review of Clinical Trials Using Neural Stem Cells. JSM Biotechnol Bioeng 3(3): 1057.
ABBREVIATIONS
ALS: Amyotrophic Lateral Sclerosis; G-SCF: Granulocytecolony Stimulating Factor; HSSC: Human Spinal cord derivedStem Cell; HuCNS-Sc: Human Central Nervous System DerivedStem Cell; INCL: Infantil Neuronal Ceroid Lipofuscinosis; iPSC: Induced-Pluripotent Stem Cell; MRI: Magnetic Resonance Imaging; NSC: Neural Stem Cell.
INTRODUCTION
Stem cells are located in a lot of tissues or organs, including blood [1], teeth [2], bone marrow [3], brain [4] and human umbilical cord blood [5]. Their main properties are to divide, renew themselves and differentiate in specialized cells types.
Currently, 5508 clinical trials using stem cells are listed on the website www.clinicaltrials.gov, of which 320 studies are in phase 3 or 4 in many diseases including bacterial and fungal, central nervous system, lung, digestive diseases or cancer. Hematopoietic stem cells from peripheral blood or bone marrow are the most used, followed by mesenchymal stem cells. Neural stem cells (NSCs) represent an important source of stem cells from brain that can differentiate into neurons, oligodendrocytes or astrocytes, and they are responsible of neurogenesis in human adult brain. Moreover, several studies showed their ability to migrate to a lesion area following brain injuries, such as neurodegenerative diseases (Alzheimer, Parkinson), strokes, or brain tumours [6,7]. Unfortunately, it seems that this capacity is too low to repair efficiently the injured tissue because no self-rescue has been shown yet in patients. These cells also represent a source for cancer stem cells, which are responsible of the tumour recurrence as they resist to current treatments [8]. Manipulating endogenous and genetically modified NSCs have been used in several studies to treat neurodegenerative disorders, spinal cord lesions, and malignant glioma [9,10]. These cells represent promising and innovative resource for anti-tumour and regenerative-based therapies in order to repair damaged brain. Here, we will review the completed or ongoing clinical trials using NSCs across the world and will describe some results of these clinical trials.
LISTING OF ALL CLINICAL TRIALS USING NEURAL STEM CELLS
Currently, there are 37 clinical trials involving NSCs in the world (Figure 1A).
Figure 1 Clinical trials using neural stem cells in the world. Distribution of clinical trials with neural stem cells by countries (A), according to diseases (B), and according their randomized phases (C). Distribution of clinical trials using endogenous neural stem cells, or derived-neural stem cells (D). Abbreviations: ALS: Amyotrophic Lateral Sclerosis; iPSCs: induced Pluritotent Stem Cells; NSC: Neural Stem Cell.
All of them are listed in tables 1 and 2.
Table 1: Clinical trials that involved neural stem cells (according to the website: www.clinicaltrials.gov). |
||||||
Identifier |
Pathology |
Phase |
Age group |
Study start |
Country |
Completion |
NCT02055196 |
Recurrent high-grade gliomas |
1 |
Adult |
np |
US |
may 2014 |
NCT01172964 |
Recurrent high-grade gliomas |
np |
Child/Adult/Senior |
2010 |
US |
feb. 2015 |
NCT01478854 |
GBM (newly diagnosed) |
np |
Adult/Senior |
2011 |
US |
jan. 2016 |
NCT00581113 |
Brain metastases |
3 |
Adult/Senior |
2007 |
US |
jun. 2009 |
NCT01251913 |
Ependymomas/Gliomas/ PNET/ Pineal Tumours/ PCNSL |
np |
Adult/Senior |
2010 |
US |
apr. 2015 |
NCT00397423 |
Amyotrophic Lateral Sclerosis |
2 |
Adult |
2006 |
CN |
aug. 2007 |
NCT01640067 |
AmyotrophicLateralSclerosis |
1 |
Adult/Senior |
2011 |
IT |
dec. 2015 |
NCT00976430 |
Parkinson |
np |
Adult/Senior |
2009 |
IN |
nov. 2011 |
NCT01321333 |
Thoracic Spinal Cord Injury |
1 / 2 |
Adult |
2011 |
CAN, CHE |
apr. 2015 |
NCT01772810 |
Spinal Cord Injury |
1 |
Adult |
2014 |
US |
mar. 2016 |
NCT02163876 |
Cervical Spinal CordInjury |
2 |
Adult |
2014 |
US, CAN |
may 2016 |
NCT01725880 |
Spinal Cord Injury |
np |
Adult |
2012 |
CHE |
may 2016 |
NCT01343511 |
Autism |
1 / 2 |
Child |
2009 |
CN |
may 2011 |
NCT01632527 |
Age-related MD |
1 / 2 |
Adult/Senior |
2012 |
US |
jun. 2015 |
NCT01432847 |
Retinal Disease |
np |
Child/Adult/Senior |
2011 |
US |
np |
NCT01238315 |
NCL |
1 |
Child |
2010 |
US |
apr. 2011 |
NCT01489267 |
Hereditary Cerebellar Ataxia |
2 |
Adult |
2011 |
CN |
july 2014 |
NCT02387749 |
DPN |
2 / 3 |
Adult |
2014 |
EG |
aug. 2016 |
Abbreviations: CAN: Canada; CHE: Switzerland; CN: China; DPN: Diabetic Peripheral Neuropathy; EG: Egypt; GBM: Glioblastoma Multiform; IN: India; IT: Italy; np: not provided; MD: Macular Degeneration; NCL: Neuronal Ceroid Lipofuscinosis; PCNSL: Primary CNS Lymphoma; PNET: Primitive Neuroectodermal Tumours; US: United States. |
Table 2: Clinical trials currently ongoing that involve neural stem cells (according to the websit0e: www.clinicaltrials.gov). |
||||||
Identifier |
Pathology |
Phase |
Age group |
Studystart |
Country |
Completion |
NCT02458508 |
Glioblastoma |
np |
Adult/Senior |
2015 |
IT |
mar. 2017 |
NCT02015819 |
Recurrent high-grade gliomas |
1 |
Adult/Senior |
2014 |
US |
oct. 2017 |
NCT02192359 |
Recurrent high-grade gliomas |
1 |
Adult |
2016 |
US |
mar. 2019 |
NCT02177578 |
GBM (newlydiagnosed) |
2 |
Adult/Senior |
2014 |
US |
jun. 2020 |
NCT01730716 |
Amyotrophic Lateral Sclerosis |
2 |
Adult/Senior |
2013 |
US |
nov. 2016 |
NCT01348451 |
Amyotrophic Lateral Sclerosis |
1 |
Adult/Senior |
2009 |
US |
dec. 2016 |
NCT01329926 |
Parkinson |
0 |
Adult/Senior |
2011 |
US |
oct. 2016 |
NCT02452723 |
Parkinson |
1 |
Adult/Senior |
2016 |
AU |
mar. 2019 |
NCT02688049 |
Spinal Cord Injury |
1 / 2 |
Adult |
2016 |
CN |
dec. 2017 |
NCT02302157 |
Spinal Cord Injury |
1 / 2 |
Adult/Senior |
2015 |
US |
sept. 2018 |
NCT02326662 |
Spinal Cord Injury |
1 / 2 |
Adult |
2014 |
RU |
dec. 2018 |
NCT02117635 |
Stroke |
2 |
Adult/Senior |
2014 |
GB |
dec. 2017 |
NCT01151124 |
Stroke |
1 |
Adult/Senior |
2010 |
GB |
mar. 2023 |
NCT01933802 |
Multiple Sclerosis |
1 |
Adult/Senior |
2014 |
US |
jun. 2017 |
NCT02720939 |
Autism Spectrum Disorder |
np |
Child/Adult/Senior |
2016 |
TWN |
dec. 2016 |
NCT01392989 |
MDS/MPD |
2 |
Adult Senior |
2011 |
US |
jan. 2018 |
NCT01916369 |
Peripheral Arterial Disease |
1 |
Adult/Senior |
2014 |
GB |
dec. 2016 |
NCT02696746 |
Channelopathies |
np |
Adult Senior |
2012 |
GB |
jan. 2019 |
NCT02336802 |
Anxiety |
np |
Adult |
2015 |
BEL |
dec. 2018 |
Abbreviations: AU: Australia; BEL: Belgium; CN: China; GB: United Kingdom; GBM: Glioblastoma Multiform; IT: Italy; np: not provided; MDS: Myelodysplastic Syndromes; MPD: Myeloproliferative Disorders; RU: Russian Federation; TWN: Taïwan; US: United States |
According to ClinicalTrials.gov, the first clinical use of NSCs started in 2006 at the Peking University, China, to treat adult patients with Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disease. Participants received an injection of a neurotrophic factor (G-CSF, Granulocyte-Colony Stimulating Factor) to stimulate the neuronal differentiation of adult NSCs in the brain [11].
Since, other clinical trials using endogenous or derived NSCs were conducted in the world to treat several brain disorders.Most of them were found in North America (19), few in Europe (United Kingdom (4), Switzerland (2), Italy (2) and Belgium (1)), and in Asia (China (4), India (1), Taiwan (1)).Isolated studies were initiated in Egypt, Australia, and Russian federation (Figure 1A). The use of NSCs in clinical trials were mainly developed against gliomas, neurodegenerative diseases (ALS and Parkinson), and spinal cord injuries. Other studies were conducted for the treatment of strokes, autism and retinal disorders (Figure 1B). Among these clinical studies, only one was in phase 3 and one in phases 2-3 (Figure 1C). Currently, 18 clinical trials are still progressing, for which first results and primary or final completion are expected in the next months or years.
Endogenous NSCs were not mainly involved in these clinical trials, whereas derived-NSCs were usually studied. Most clinical trials used NSCs derived from different cell lines, such as HuCNSSC®, CTX DP, HB1.F3.CD, hCE1m6, ISC-hpNSC, or AST-OPC1. Several studies also used mesenchymal stem cell-derived NSCs, human spinal cord-derived NSCs, induced pluripotent stem cells (iPSCs), or human foetal-derived NSCs. Only 5 clinical trials involved endogenous NSCs (Figure 1D).
SOME EXAMPLES OF CLINICAL TRIALS WITH NEURAL STEM CELLS
The first study using NSCs on children was in 2006 for infantile neuronal ceroid lipofuscinosis (INCL) (NCT00337636) [12]. This disease can affect the brain and the retina of persons from infancy to adulthood age. In juvenile, it is caused by mutation in the CLN1 gene, which codes for a lysosomal protein. This mutation leads a loss of vision and blindness, epilepsy, motor coordination problems or emotional reactions like depression [13]. Human central nervous system-stem cells (HuCSN-SCs), in vitro, had been showed to secrete the enzyme deficient in INCL. In this clinical trial, HuCNS-SCs from single human foetal brain tissue have been transplanted in each lateral ventricle of infants. The procedure seemed both safe and well accepted by children. Only transitory moderate or severe adverse effects were observed, and these were not directly attributed to the transplantation. Importantly, discovery of HuCNS-SCs in post-mortem host brain 1-year after transplantation and long after the cancellation of immunosuppression suggested that this approach has a therapeutic potential for the treatment of human neurodegenerative disease, in children but also in adult. Currently, this investigation measures the post-transplantation disease progression under clinical trial protocol n°NCT01238315.
The ALS is a neurodegenerative disease caused by a progressive degeneration of motor neurons. The death is generally caused by respiratory failure few years after the appearance of first symptoms. The dysphagia and pneumonia are the most important symptoms, which both reach the life quality of patients. There is no cure for this disease except some management to reduce symptoms or the Riluzole® administration which counteracts the excitotoxicity and allows a low survival improvement (3-6 months) [14]. Thirty clinical trials have started with different stem cells (hematopoietic, mesenchymal, neural or again adipocyte-derived stem cells). Three studies were well documented with NSCs that we will describe here. The two first clinical trials (NS2008-1 and NCT01348451) used NSCs isolated from the cervico-thoracic spinal cord-derived from an 8-week gestation foetus (NSI-566RSC cell line). They were isolated and propagated in vitro in serum-free medium until 25 passages and used to be injected in patients. These human spinal cord-derived stem cells (HSSCs) have been used in clinical trials for 15 patients with ALS [15,16]. In these two trials, HSSCs were injected five times into the lumbar or cervical segments of the spinal cord of ALS patients by unilateral or bilateral injections. 6 patients received first either unilateral or bilateral lumbar injection [15]. In the second part of the trial, 3 patients who had already received bilateral injection in lumbar, received unilateral injection in cervical and 3 other patients received unilateral cervical injection [16].
The goal of these studies was to show the safety and tolerability of injection in lumbar or cervical spinal cords of patients and check the dual-targeting approach. Firstly, some adverse events were noted like encephalopathy, bronchitis and pneumonia but these side effects were due to the ALS diseases. Most patients had mild and transient pain but the major toxicity was related to immunosuppressant drugs given to all patients. There was no evidence for decline in function or acceleration of progression after surgical intervention. More than 50%of patients had better outcomes than baseline until 15 months post-operation. Despite 7 deaths unrelated to HSSC use, the injection of stem cells in lumbar and cervical spinal cord of patients with ALS represented a significant advance in the cell therapy field. Survived-patients showed a slower progression of the disease and functional improvement. The three subjects who received more injections (bilateral and unilateral injections in lumbar and cervical, respectively) demonstrated the largest effects on progression rates, suggesting the beneficial of multiple injections. Following these clinical trials, phase 2 trial started in September 2013 (Protocol n° NCT01730716).
Another Phase 1 clinical trial started in 2012 (clinical trial number: NCT01640067) with ALS patients and similar transplantation method [17]. However, human NSCs were isolated from forebrain at gestational ages greater than 8th post-conceptional week with spontaneous in utero death. This source of cells could be more ethic because cells were recovered following miscarriage. Moreover, 5 times more cells were transplanted (750000 cells per patient) than the previous clinical trial described above (100 000 cells per patient) [16]. The goal of this study was to approve the safety of both cells and procedure of transplantation. No severe side effect was found except pain near the injection site, and the MRI did not show structural changes or tumour formation in brain or spinal cord after transplantation. This clinical trial reproduced the results from the previously quote clinical trial using other cells. Now, intraspinal injection was evaluated into the cervical spinal cord of 12 ambulatory patients with ALS.
Several investigations showed that NSCs and progenitor cells present in the subventricular zone of brain bearing glioblastoma represent potential tumour-initiating cells (cancer stem cells) associated with a higher recurrence rate and shorter overall survival [18,19]. In the United States, a recent randomized phase 2 clinical trial, with primary completion in June 2020 (NCT02177578), is currently conducted in newly diagnosed glioblastoma patients, in order to treat endogenous NSCs in the subventricular zone with modified radiation treatment in addition to the standard chemotherapy (Temozolomide). A group of patients is treated with a higher radiation therapy plan, both directed against tumour and subventricular zone. And the control group is treated with standard radiation therapy, only directed against the tumour. The aim of this study is to examine the progression free survival between these two groups. Several other studies concerning brain diseases like cerebellar atrophy [20], spinal cord injury [21], Pelizaeus-Merzbacher disease [22] or cerebral palsy [23] also showed safety of the procedure and efficiency of autologous or allogenic stem cells transplantation after expansion in vitro.
DISCUSSION & CONCLUSION
As documented above, derived-neural stem cells are mainly used for brain disorders like cancers, neurodegenerative diseases or diseases from the peripheral nervous system. Collecting endogenous NSCs cells directly from the brain is complicated and the use of derived-NSCs from other stem cells could lead mutation issues. One of the best strategies to reach NSCs without taking them out from their environment would be to target NSCs directly in the brain by intra-ventricular injection. Several experimental procedures were recently developed to target in vitro and in vivo NSCs and to induce their differentiation. For instance, aneurofilament derived-peptide, named NFL-TBS.40-63, is able to target NSCs from the subventricular zone. Moreover, in vitro the peptide decreased the self-renewal and proliferation of NSCs cells while their adhesion and differentiation were increased [24]. Another study showed that the forced neuronal differentiation of glioblastoma stem-like cells with neurogenic transcription factors inhibited their capacity to form orthotopictumour in vivo [25]. Glioblastoma stem cells are implicated in the tumour recurrence and thus in the low survival rate of patients. Targeting these cells is a promising approach to treat this disease [26].
As describe above, the first clinical trial using a factor to stimulate endogenous NSCs started in 2006 in China in a cohort with ALS patients. This clinical trial in phase 2 was finished since 2007 (according to the website clinicaltrials.org), but no results are available. Since the first clinical trial involving NSCs in 2006, 36 others clinical trials came out, and only one is in phase 3. Unfortunately, most studies are outdated and only few results are published. The most promising strategy would be to target endogenous NSCs directly in the brain of patients by intraventricular injection to induce the differentiation in the case of neurodegenerative diseases or to stop their migration and tumorigenesis in the case of tumour.
ACKNOWLEDGMENTS
This work was supported by AFM (Association Françaisecontre les Myopathies, ARC (Association de Recherchecontre le Cancer), CIMATH (CiblageMoléculaireetThérapeutique), MATWIN(Maturation & Accelerating Translation with Industry), and by UNAM (Université Nantes, Angers, Le Mans).
Barreau Kristell is supported by a grant of the University of Angers, in the framework of NanoFar “European Doctorate in Nanomedicine” EMJD programme funded by EACEA. LépinouxChambaud Claire is supported by the “Société d’Accélération du Transfert de Technologie (SATT) Ouest Valorisation“.
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