Clinical translation of human neural stem cells
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Human neural stem cell transplants have potential as therapeutic candidates to treat a vast number of disorders of the central nervous system (CNS). StemCells, Inc. has purified human neural stem cells and developed culture conditions for expansion and banking that preserve their unique biological properties. The biological activity of these human central nervous system stem cells (HuCNS-SC®) has been analyzed extensively in vitro and in vivo. When formulated for transplantation, the expanded and cryopreserved banked cells maintain their stem cell phenotype, self-renew and generate mature oligodendrocytes, neurons and astrocytes, cells normally found in the CNS. In this overview, the rationale and supporting data for pursuing neuroprotective strategies and clinical translation in the three components of the CNS (brain, spinal cord and eye) are described. A phase I trial for a rare myelin disorder and phase I/II trial for spinal cord injury are providing intriguing data relevant to the biological properties of neural stem cells, and the early clinical outcomes compel further development.
KeywordsSpinal Cord Injury Fractional Anisotropy Neural Stem Cell Retinal Pigment Epithelial American Spinal Injury Association
American Spinal Injury Association
Central nervous system
Food and Drug Administration
Human central nervous system stem cells
Lysosomal storage disease
Myelin basic protein
Magnetic resonance imaging
Neuronal ceroid lipofuscinosis
Polymerase chain reaction
Royal College of Surgeons
Retinal pigmented epithelial
Spinal cord injury
Immunodeficient Shi mice.
StemCells, Inc. was formed with the charter of discovering tissue-derived stem cells using the monoclonal antibody-based high speed cell sorting technology platform, previously used for purification of hematopoietic stem cells and peripheral nervous system stem cells [1, 2, 3, 4]. More recently, this technology has been used to identify and purify other tissue stem cells, including hair follicle and skin , intestinal , muscle  and cancer stem cells [8, 9]. This technology can also be applied to the purification of multi-potent stem cell populations derived from embryonic or induced pluripotent stem cells to eliminate teratogenic precursors. The company employed this strategy to prospectively purify its human central nervous system stem cell (HuCNS-SC®) population for expansion as neurospheres and banking. In this overview, the preclinical data are summarized and rationale provided for advancing these cells into clinical trials involving the brain, spinal cord, and eye.
A seminal finding in advancing regenerative medicine for human neurological disorders was the demonstration that neurogenesis occurs in the human adult brain [10, 11]. This discovery, coupled with the identification and expansion of human neural stem cells by our laboratory and others [12, 13, 14, 15, 16, 17, 18], has led to a plethora of studies investigating neuroplasticity and regeneration. Though still early, a growing body of data suggests that human neural stem cells or their progenitors might one day repair or replace cells within the diseased or damaged central nervous system (CNS).
The translation of HuCNS-SC to clinical testing has been facilitated by prospective identification, reproducible expansion into cell banks, and stability upon cryopreservation. The availability of small animal models relevant to a range of human conditions has further facilitated efficacy testing and investigation of potential mechanisms of action. Moreover, past experience with cell and tissue transplants into the brains of Parkinson’s or Huntington’s patients (reviewed in [19, 20, 21]) has provided insights into allogeneic long-term survival in the relative immune-privileged niche of the CNS and has paved the way for studies with neural stem and/or progenitor cell products.
About the human central nervous system stem cells
The existence of both mouse and human neural stem cells has been demonstrated by multiple laboratories through growth in tissue culture systems and multi-lineage differentiation in fate mapping studies of cultured cells [22, 23, 24, 25, 26, 27]. In 2000, scientists at StemCells, Inc. purified HuCNS-SC [16, 28], an adult, tissue-specific stem cell. Each HuCNS-SC bank is created from purified human neural stem cells from a single fetal brain tissue (16 to 20 weeks gestation) using an isolation protocol involving monoclonal antibodies to cell surface markers and high-speed cell sorting. The cell expresses high levels of CD133 and low levels of CD24 (CD133+/CD24-/lo) and lacks expression of the hematopoietic lineage markers CD45 or CD34. Single CD133+/CD34- CD45- sorted cells can self-renew to form neurospheres with multi-potentiality, hence the qualification as a ‘stem cell’. When the CD133+/CD24-/lo cells are grown under defined conditions , long-term expandable neurosphere cultures are established. Karyotype and morphological stability have been demonstrated with more than ten passages and in long-term culture. This method of cell isolation and culture has allowed for reproducible generation of human neural stem cell banks. For human clinical application, brain tissues are procured through an approved non-profit tissue procurement agency according to the Good Tissue Practice requirements of the US Food and Drug Administration (FDA).
Overview of HuCNS-SC clinical translation programs for central nervous system disorders
Neuronal ceroid lipofuscinosis (Batten disease): infantile and late-infantile
Phase I completed
Safety, feasibility and tolerability of HuCNS-SC transplants. Post-mortem evidence of long-term donor cell survival in post-mortem 3/6 subjects alive 5 years post-transplant
Phase Ib suspended
No accrual of eligible subjects
Pelizaeus-Merzbacher myelin disorder
Phase I completed
MRI evidence of donor-derived myelin and modest gains in neurological function
Enhanced synaptic function and restored memory in two AD relevant models
Thoracic spinal cord injury
Phase I/II in progress
Sensory gains observed in first cohort.
Cervical spinal cord injury
Improve motor function in SCI mice
Age related macular degeneration
Phase I/II in progress
Subject accrual ongoing
Disease targets for neuroprotective and neuronal replacement strategies
Neuroprotection of host cells can result from several mechanisms, including provision of neurotrophic, angiogenic, immune modulating factors and/or other proteins required for maintenance of healthy neurons. Protection of host neurons can also result from remyelination from new oligodendrocytes. Neuronal replacement strategies aim to replace specific lost or deficient cells, such as in Parkinson’s disease. The key attributes of neural stem cells - such as self-renewal to provide a continuous reservoir of factor-producing cells, global CNS migratory properties, and their innate ability to form new normal neurons, astrocytes or oligodendrocytes - position them as attractive novel therapeutics for treating the plethora of neurodegenerative conditions. The translational approach was to first test the neuroprotective properties of the stem cell in the initial introduction to human testing while continuing to accumulate more complex preclinical data supporting neural replacement strategies. The first application of HuCNS-SC as a therapeutic candidate evaluated its safety and preliminary efficacy as a cell-based enzyme delivery system in a neurodegenerative lysosomal storage disease (LSD).
Lysosomal storage diseases affecting the central nervous system
LSDs result from recessive mutations in genes encoding soluble enzymes or structural proteins causing lysosomal dysfunction, accumulation of insoluble storage material, and eventual cell death. Development of effective therapies for the neuropathic LSDs, such as enzyme replacement, is challenged by the presence of the blood-brain barrier, which limits accessibility of intravenously delivered soluble enzyme to the brain. Direct intrathecal and intracisternal delivery of enzyme, protein modifications (such as lipidization and receptor targeting), nanotechnologies, as well as cell-based delivery schemes are all being tested for more effective transport of proteins and drugs to the CNS but currently no strategy has hit a home-run . The concept of using neural stem cells for the delivery of normal proteins to replace those that are defective or absent was proposed to take advantage of the inherent properties of these cells (reviewed in ). Their long-term integration and global distribution throughout the brain parenchyma comprise a mechanism to deliver therapeutic proteins in a direct and sustained manner. Several studies have examined the effect of normal or genetically engineered neural stem cells in specific animal models of LSDs [32, 33, 34, 35, 36, 37, 38, 39] and shown these to be viable therapeutic strategies worthy of further investigation.
Neuronal ceroid lipofuscinoses
Of the numerous LSDs, neuronal ceroid lipofuscinoses (NCLs; commonly referred to as Batten disease) exhibit disease pathogenesis predominantly within the CNS. NCLs comprise the most prevalent group of neurodegenerative LSD and consist of at least ten genetically distinct forms. The infantile (CLN1, palmitoyl-protein thioesterase, PPT-1 enzyme deficiency) and late-infantile (CLN2, tripeptidyl-peptidase I, TPP-I enzyme deficiency) genetic subtypes result from gene mutations in soluble lysosomal enzymes [40, 41] causing accumulation of lipofuscin material in neurons and eventual cell death. Knockout mouse models for the infantile (PPT1-/-)  and late-infantile (TPP-I)  forms develop progressive and severe neurodegeneration and recapitulate the pathology of the human diseases. As predicted, in vitro preclinical studies show HuCNS-SC-based cross-correction of enzyme deficiency through PPT-1 uptake via the mannose 6-phosphate receptor in cultured PPT-1-deficient mouse and human fibroblasts . In order to create a suitable xenotransplantation model for testing the long-term effects of HuCNS-SC, the PPT-1 knockout mouse was backcrossed to the immune deficient NOD-SCID mouse. Transplantation of HuCNS-SC in the PPT-1 knockout/NOD-SCID brain results in engraftment, migration and a region-specific differentiation pattern similar to that observed in non-neurodegenerative NOD-SCID animals. The HuCNS-SC transplanted mice showed production of functional PPT1 enzyme in whole brain extracts and statistically significant reduction in lipofuscin levels, ranging from 31% in the cortex to >50% in the hippocampus and cerebellum. The reduction in storage material correlated with observed protection of hippocampal neurons (up to 57% of CA1 and 97% of CA2/3) and up to 77% of cortical neurons. The neuroprotective effects of HuCNS-SC transplants through cell-based enzyme cross-correction also delayed the loss of motor function. These data provided the rationale for the first in-human trials using these purified and expanded, allogeneic human neural stem cells.
This clinical trial represents the first demonstration that purified, expanded and cryobanked, allogeneic human neural stem cells can be safely transplanted directly into the brain and are well tolerated in severely afflicted pediatric subjects. Neuropsychological outcomes did not show improvement in the subjects with refractory disease, and alterations in disease course could not be determined in this uncontrolled study. It was noted, however, that patients with the most cerebral atrophy and neurological disability continued to decline whereas those less impacted showed stability . Moreover, the 4-year follow-up of the remaining subjects continues to show a satisfactory safety profile with no emerging safety concerns.
For a neuroprotective strategy to show meaningful clinical outcomes, sufficient numbers of functional host cells must exist at the time of intervention, hence the need to transplant subjects earlier in their disease course. A phase Ib trial in NCL was initiated to examine safety in subjects with early disease and also to determine the impact of HuCNS-SC transplantation on disease progression. The study was suspended before enrolling any subjects due to a lack of available study candidates with less pronounced neurodegeneration at presentation. Of the 22 potential subjects for possible screening, none met the inclusion criteria for the trial. The inability to accrue subjects in clinical trials for rare diseases is a challenge at best, as identifying those earlier in the disease course is compounded by significant delays in proper diagnosis. Establishment of more rapid methods to diagnose genetic diseases in newborns  is needed to shorten times to diagnosis and clinical decision making for relevant treatment options.
Normal function of the nervous system requires formation and maintenance of the myelin sheath, the insulating layer surrounding nerve axons required for rapid conduction of electrical impulses and axonal integrity. Dysfunction or loss of myelin can lead to severe deficits in neurological function as seen in the leukodystrophies, multiple sclerosis, stroke, and traumatic brain and SCIs. One strategy to preserve neuronal function is through provision of new myelinating oligodendrocytes and supportive astrocytes derived from neural stem cells  or glial progenitor cells (reviewed in [48, 49]).
Several animal models exist for testing treatment options for myelin disorders, each possessing unique attributes or aspects reflective of the human afflictions (reviewed in ). The myelin basic protein (MBP)-deficient shiverer (Shi) mouse is a dysmyelination model widely used to assess myelin production by donor cells [51, 52, 53, 54, 55, 56]. The Shi mouse has been crossed to immunodeficient strains to facilitate analysis of transplanted human xenografts [47, 53, 54, 57, 58]. De novo myelin production from human oligodendrocytes has been observed in the brains of immunodeficient Shi mice (Shi-id) or contused SCI NOD-SCID mice transplanted with HuCNS-SC [47, 54]. In these studies, immunohistochemical staining demonstrated that host mouse axons were ensheathed by human myelin derived from transplanted HuCNS-SC. Generation of compact myelin in the injured spinal cord correlated with improved motor function and in the Shi-id brain restored CNS conduction velocity in animals transplanted as asymptomatic neonates or symptomatic hypomyelinated juveniles. Moreover, ex vivo magnetic resonance imaging (MRI) of transplanted Shi-id brains detected changes in water diffusivity consistent with increased myelination. In the rodent brain, robust human MBP expression is observed at approximately 6 weeks after HuCNS-SC transplantation . Thus, while other myelin mutant models of human diseases exist, such as the proteolipid protein (PLP) mutants reflective of Pelizaeus-Merzbacher disease (PMD), their shortened life span precludes assessment of the robustness and longevity of neural stem cell-based therapies. The preclinical demonstration of de novo myelination from transplanted HuCNS-SC in the Shi-id mouse and the contused SCI NOD-scid mouse provided the rationale to obtain FDA authorization for a phase I/II study in PMD.
PMD is a rare fatal leukodystrophy resulting from mutations of the X-linked gene encoding PLP1, the major protein of the CNS myelin sheath. PLP1 mutations produce a spectrum of neurological symptoms ranging from severe, or connatal form, to classical, or the milder spastic paraplegia, all resulting from failure to produce functional myelin either due to apoptosis of the oligodendrocytes or abnormal myelin formation . In the most severe connatal group, clinical signs of PMD can present at birth or within the first few weeks as nystagmus (uncontrolled rapid eye movements), difficulty breathing and low muscle tone (hypotonia). The subjects often require a tracheostomy to assist in airway management and a gastrostomy tube shortly after birth. Neurological and developmental milestones are either delayed or never achieved. Patients have severe motor and language impairment, which generally progresses. The onset of severe spasticity can be seen in later childhood. MRI reveals diffuse hypomyelination of both cerebral hemispheres, brainstem and cerebellum. There are no therapeutic options for patients with PMD; only supportive and palliative treatments are available. Death usually occurs within the first decade of life.
Major neurological and MRI diffusion changes, by subject, for the phase I trial in Pelizaeus-Merzbacher disease
Neurological and radiological changes
Subject 1 (16 m of age at transplant)
Tracheostomy and gastrostomy at baseline
Remained neurologically stable, but was noted to have reduced nightly CPAP at 12 months
Increased FA by MRI
Subject 2 (42 m of age at transplant)
Developed improved truncal support and the ability to take steps with assistance. He also began speaking audible single words and the ability to follow two-step commands
Increased FA by MRI
Subject 3 (14 m of age at transplant)
Tracheostomy and gastrostomy at baseline
Developed upper extremity antigravity strength and to take some solid foods by mouth
Nightly CPAP dependency reduced
Greatest increase in FA by MRI; but comparable to ‘control’ regions
Subject 4 (66 m of age at transplant)
Developed improved truncal support and progressed from the use of a walker with significant support at baseline to walking with minimal assistance
Developed the ability for self-feeding and to follow two-step commands
Increased FA by MRI
Spinal cord injury
Traumatic SCI results in localized destruction of neural tissue from the primary injury followed by secondary injury from inflammation, immune responses and cell apoptosis. These events result in oligodendrocyte death and axonal loss in white matter and neuronal loss in gray matter. Neural stem cell transplantation for SCI represents a unique opportunity to assess an inherent multipronged therapeutic strategy that demonstrated improvement in locomotion in preclinical animal models. Human neural stem cells can provide neuroprotection through provision of secreted neurotropic and angiogenic factors and/or re-formation of myelin sheaths from stem cell-derived oligodendrocytes for maintenance of axonal integrity. The transplanted neural stem cells may also contribute to neuroreplacement by differentiating neurons capable of creating synaptic contacts to re-establish bridging circuitry between new neurons and host cells .
Our collaborators at the University of California, Irvine, Drs Anderson and Cummings, developed thoracic SCI models in immunodeficient mice to examine the efficacy, mechanism of action, and long-term survival of HuCNS-SC transplants into subacute or chronic injured cords [54, 61, 62, 63]. The cumulative data spanning approximately 10 years shows that HuCNS-SC transplanted directly into the cord above and below the epicenter of injury restored locomotor function in subacute and chronic SCI mice. Analysis of transplanted spinal cords by dual histochemical staining for human cells and lineage markers showed robust engraftment, migration and differentiation to neurons (26 to 38%), astrocytes (3 to 8%) and oligodendrocytes (48 to 64%) [54, 63]. Immunoelectron ultrastructural analysis reveals the formation of compact myelin sheaths by human oligodendrocytes as well as human neurons with synaptic vesicles juxtaposed to host neurons. These results suggest that multiple mechanisms of action may be contributing to functional recovery in these animals. Although the ability to dissect this question remains challenging, one clue to potential mechanisms of action comes from selective ablation of the human cells using diphtheria toxin, which abrogates the regained motor function. This study shows the requirement for continued integration and survival of human cells to maintain restored motor function. Thus, the therapeutic effects of HuCNS-SC seen in SCIs and a hypomyelination disease results from stable integration of newly formed neural cells, in particular myelin-producing oligodendrocytes. In fact, these cells likely impart their full therapeutic potential as a result of both integration and function, as well as provision of neurotrophic support. Another important aspect of these studies was the lack of induced allodynia (abnormal sensitivity to pain) following HuCNS-SC transplantation. These results contrast with those previously reported  in which neural stem cell transplants led to functional recovery of hind limbs but development of hypersensitivity (allodynia) in the forepaws due to axonal sprouting. Differences in cell source, animal models and culture methods preclude identification of specific parameters that contribute to the undesired outcome in their study. The positive impact on locomotion coupled with the lack of safety concerns of the purified, expanded and banked HuCNS-SC in the immunodeficient SCI model provided the rationale for initiation of a clinical study in thoracic SCI subjects.
A progressive clinical study design was implemented by the company to test the safety and clinical effects of HuCNS-SC transplants in subjects with chronic thoracic (T2-T11) complete injury (American Spinal Injury Association (ASIA) classification A) progressing to subjects with incomplete (ASIA B or C) injury. The phase I/II trial was authorized by the SwissMedic regulatory authority and is being conducted by Dr Armin Curt (Balgrist Hospital, University of Zurich). The study will enroll 12 subjects who sustained a SCI within 3 to 12 months prior to cell transplantation. Each subject will receive a total fixed dose of approximately 20 million cells injected directly into the thoracic cord near the injury. Dosing of the first cohort, three AISA A subjects, has been completed and a 6-month interim evaluation performed (A Curt, Annual Scientific Meeting of the International Spinal Cord Society, September, 2012). To date, no safety concerns have arisen concerning the surgery or cellular transplant. Considerable gain in sensory function below the injury level was observed in two of the three subjects. This increased sensitivity to touch has evolved over time and was not anticipated in these very severely injured subjects since they were neurologically stable before transplant. Parallel changes in sensitivity to heat and electrical stimulation were also observed. Electrophysiological measurements across the injured spinal segments provided independent and objective measures of the change in sensory function. These data suggest that the transplanted human neural stem cells may be having a positive clinical effect in these severely injured subjects. The trial has just completed dosing of the first incomplete ASIA B subject and will continue to enroll eligible subjects until trial completion. Most human SCIs involve the cervical regions and preclinical studies are currently in progress with HuCNS-SC transplants into rodent models of cervical cord hemi-contusions in support of advancement to clinical testing.
The retina is an integral component of the CNS with complex neural circuitry involving transmission of signals from the photoreceptors to the brain through the optic nerve. Retinal diseases have long been viewed as a prime target for consideration in transplantation approaches because of ease of access, out-patient surgical procedure, the size of the eye, and the availability of non-invasive tests for visual function assessment following cell transplantation. Photoreceptors and retinal pigmented epithelial (RPE) cells derived from pluripotent stem cells have been the lead candidates for strategies based on cell replacement [65, 66].
The study consists of two cohorts of 8 subjects (16 total). Cohort 1 will enroll subjects with best corrected visual acuity levels of ≤20/400 in the treated eye. The second cohort will enroll subjects with best corrected visual acuity of 20/200 to 20/100. The subjects will receive oral immunosuppression for 3 months after surgery and will be followed for 1 year for any adverse events. Secondary assessments for preliminary efficacy will include visual acuity testing, and other detailed evaluations of ocular function and retinal imaging. At the conclusion of the study, subjects will be asked to participate in a separate 4-year long-term follow-up study.
Targets for the future
The translational studies of HuCNS-SC speak to the biological activity of these cells in the brain, spinal cord and eye. To date, the preclinical studies in specific animal models have revealed biological properties of the HuCNS-SC similar to the emerging human data in the early clinical studies. The ultimate demonstration of a confirmed effect in patients will require controlled studies but the first results on safety and preliminary effects from these trials provide justification for continued human testing. Evidence of de novo myelin production in a hypomyelination disorder and improved sensation in SCI as clinical endpoints, unobserved with other interventions, emphasizes the potential of neural stem cell transplantation. If neural stem cell transplantation continues to show promising clinic data in altering disease progression, this approach could provide the novel therapeutic modality sorely needed for a spectrum of challenging neurological disorders.
This article is part of a thematic series on Clinical applications of stem cells edited by Mahendra Rao. Other articles in the series can be found online at http://stemcellres.com/series/clinical.
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