Neurosurgery. 2010 Dec 16. [Epub ahead of print]

Autologous Bone Marrow Mononuclear Cell Therapy for Severe Traumatic Brain Injury in Children.


Cox CS Jr, Baumgartner JE, Harting MT, Worth LL, Walker PA, Shah SK, Ewing-Cobbs L, Hasan KM, Day MC, Lee D, Jimenez F, Gee A.

From the University of Texas Medical School at Houston, Departments of Pediatric Surgery, Surgery, Pediatrics, and Diagnostic & Interventional Imaging; Children’s Memorial Hermann Hospital; University of Texas M.D. Anderson Cancer Center, Department of Pediatrics, Division of Cell Therapy; Baylor College of Medicine Center for Cell and Gene Therapy.

Abstract
BACKGROUND: Severe traumatic brain injury (TBI) in children is associated with substantial long-term morbidity and mortality. Currently, there are no successful neuroprotective/neuroreparative treatments for TBI. Numerous pre-clinical studies suggest that bone marrow derived mononuclear cells (BMMNCs), their derivative cells (marrow stromal cells), or similar cells (umbilical cord blood cells) offer neuroprotection.
OBJECTIVE: To determine if autologous BMMNCs are a safe treatment for severe TBI in children.
METHODS: Ten children aged 5-14 years with a post-resuscitation GCS of 5-8 were treated with 6X10 autologous BMMNCs/kg body weight delivered intravenously within 48 hours after TBI. To determine safety of the procedure, systemic and cerebral hemodynamics were monitored during bone marrow harvest; infusion related toxicity was determined by pediatric logistic organ dysfunction (PELOD) scores, hepatic enzymes, Murray lung injury scores, and renal function. Conventional magnetic resonance imaging (cMRI) data were obtained at 1 and 6 months post-injury, as were neuropsychologic and functional outcome measures.

RESULTS: All patients survived. There were no episodes of harvest related depression of systemic or cerebral hemodynamics. There was no detectable infusion related toxicity as determined by PELOD score, hepatic enzymes, Murray lung injury scores, or renal function. cMRI imaging comparing gray matter, white matter, and cerebrospinal fluid (CSF) volumes showed no reduction from 1-6 months post injury. Dichotomized Glasgow Outcome Score (GOS) at 6 months showed 70% with good outcomes and 30% with moderate to severe disability.

CONCLUSION: Bone marrow harvest and intravenous mononuclear cell infusion as treatment for severe TBI in children is logistically feasible and safe.

Thu, 07/08/2010 – 12:31 — admin

Medical College of Gergia has worked for a number of years using adult stem cells (provided by Athersys, Inc) in the experimental treatment of brain injury in an animal model.  These cells improve the outcome from acute brain injury in the animals.  In order to show that these cells have the potential to treat cerebral palsy in children, however, we need to demonstrate their effectiveness in chronic brain injury.  The use of a model with a chronic brain injury is necessary in order to mimic what happens in cerebral palsy.  We are now working to produce an animal model in infant rats which has neurological deficits persisting for an extended or chronic period.  We will soon use the Athersys adult stem cells in an effort to treat these animals.  If the treatment is successful, we hope the cells would be approved for a clinical trial in children with cerebral palsy. – Dr. James Carroll Chief of Pediatric Neurology at Medical College of Georgia

Update:
The results of the study on multipotent adult progenitor cells (MAPC).
GHS Stem Cell Study Results

There is accumulating evidence that shows that the placement of hematopoietic cells in the brain may increase growth-enhancing factors of axons and generate active neurons in the receptor. It has been found that after introducing hematopoietic cells in the subarachnoid space of the spinal cord, these cells may be transported through the cerebrospinal fluid and can be deliver more efficiently to the injured area, when compared to the intravenous route. Patients will be stimulated 5 times and then harvest the bone marrow. Bone marrow will be processed in order to obtain hematopoietic cells (CD34+) and minimize the erythrocytes amount. A inoculum of 8 to 10mL of stem cells will be infused intrathecally. Patients will be evaluated with the “Battelle Developmental Inventory” before the procedure and one and three months after that. – Dr. Mancias-Guerra University Hosiptial Monterrey MX.

The purpose of this pilot study is to evaluate the safety and feasibility of infusions of autologous (the patient’s own)umbilical cord blood cells in term gestation newborn infants with hypoxic-ischemic encephalopathy. For this study, infants who have signs of moderate to severe encephalopathy at birth whose mothers have previously consented to providing cord blood cells for the Carolinas Cord Blood Bank or other public or private bank that uses accepted standards for collection and handling of cells, or provided verbal consent for cord blood collection for the possibility of their baby’s participation in this trial, can receive their own cord blood cells if an adequate number of cells that meet Carolinas Cord Blood Bank Quality standards are available in the first 14 postnatal days. Study activities also include serial blood draws concurrent with clinically indicated blood draws with a total volume of no more than 5 milliliters (1 teaspoon) from all study related tests. Babies will be followed for neurodevelopmental outcome at 4 – 6 and 9 – 12 months at Duke’s Special Infant Care Clinic. MRI’s will be obtained between postnatal weeks 1 and 4, and, for study purposes at 4 – 6 postnatal months.

Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function.

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ.

Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.

Abstract

Birth asphyxia is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. We show that a single mesenchymal stem cell treatment at 3 d (MSC-3) after neonatal hypoxia-ischemia (HI) in postnatal day 9 mice improved sensorimotor function and reduced lesion size. A second MSC treatment at 10 d after HI (MSC-3+10) further enhanced sensorimotor improvement and recovery of MAP2 and MBP (myelin basic protein) staining. Ipsilateral anterograde corticospinal tract tracing with biotinylated dextran amine (BDA) showed that HI reduced BDA labeling of the contralateral spinal cord. Only MSC-3+10 treatment partially restored contralateral spinal cord BDA staining, indicating enhanced axonal remodeling. MSC-3 enhanced formation of bromodeoxyuridine-positive neurons and oligodendrocytes. Interestingly, the second gift at day 10 did not further increase new cell formation, whereas only MSC-10 d

Nasal administration of stem cells: a promising novel route to treat neonatal ischemic brain damage.

van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ.

Laboratory for Neuroimmunology and Developmental Origins of Disease [C.T.J.V., A.K., C.J.H.;, Department of Neonatology [C.T.J.V., F.B.], University Medical Center Utrecht,, 3584 EA Utrecht,, The Netherlands.

Abstract

Mesenchymal stem cell (MSC) transplantation is a promising therapy to regenerate the brain after an ischemic event. We investigated the possibility to use the nasal route as a non-invasive method to repair the neonatal damaged brain. Nine-day old mice underwent cerebral hypoxia-ischemia (HI) and MSC were transplanted intranasally 10 days after HI. At 28 days after HI, MSC were still present in the affected hemisphere, but had not differentiated into cerebral cell types. Intranasal MSC-treatment significantly improved sensorimotor function in the cylinder rearing test at 21 and 28 days after HI. Furthermore, intranasal MSC-treatment decreased grey and white matter area loss when determined 28 days after HI by 34% and 37% respectively. MSC cultured in vitro with brain extracts obtained 10 days after HI, responded to the ischemic brain by upregulation of several growth factors, including FGF2 and NGF in comparison to brain extracts of sham-operated controls. In conclusion, MSC can reliably be delivered to the brain via the nasal route to induce functional recovery as well as a reduction in brain lesion size. We propose that MSC function by stimulating endogenous cerebral repair by adapting their secretion profile to the ischemic brain leading to upregulation of repair promoting factors. ABBREVIATIONS::

PMID: 20639794 [PubMed - as supplied by publisher]

id. These findings indicate that increased positive effect of MSC-3+10 compared with MSC-3 alone is mediated via distinct pathways. We hypothesize that MSCs adapt their growth and differentiation factor production to the needs of the environment at the time of intracranial injection. Comparing the response of MSCs to in vitro culture with HI brain extracts obtained at day 10 from MSC-3- or vehicle-treated animals by pathway-focused PCR array analysis revealed that 29 genes encoding secreted factors were indeed differentially regulated. We propose that the function of MSCs is dictated by adaptive specific signals provided by the damaged and regenerating brain.

Mon, 10/25/2010 – 08:22 — admin

A Randomized Study of Autologous Umbilical Cord Blood Reinfusion in Children With Cerebral Palsy

This study is currently recruiting participants.

Verified by Duke University, June 2010

First Received: June 17, 2010   No Changes Posted

Purpose

The purpose of this study is to determine the efficacy of a single intravenous infusion of autologous umbilical cord blood (UCB) for the treatment of pediatric patients with spastic cerebral palsy.

Resource links provided by NLM:

MedlinePlus related topics: Cerebral Palsy Paralysis

U.S. FDA Resources

Further study details as provided by Duke University:

Primary Outcome Measures:

The primary measure of efficacy will be improvement of standardized measures of neurodevelopmental function. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

A secondary objective is to determine effects on quality of life in these children. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

A secondary objective is to describe functional and morphologic changes on brain MRI in these children. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

A secondary objective is to ask whether there is a correlation between clinical response and RNA expression of neural, endotheial and inflammatory cytokines measured by RNA arrays in cord blood cells given to these patients. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

Detailed Description:

Cerebral palsy results from in utero or perinatal injury to the developing brain, often through stroke, hypoxic insult or hemorrhage. Currently available treatments for patients with cerebral palsy are supportive, but not curative. Umbilical cord blood (UCB) has been shown to lessen the clinical and radiographic impact of hypoxic brain injury and stroke in animal models. UCB also engrafts and differentiates in brain, facilitating neural cell repair, in animal models and human patients with inborn errors of metabolism undergoing allogeneic, unrelated donor UCB transplantation. We hypothesize that, in the setting of brain injury, infusion of autologous UCB will facilitate neural cell repair resulting in improved function in pediatric patients with cerebral palsy.

Eligibility

Criteria

Inclusion Criteria:

Age ≥ 12 months and ≤ 6 years

Diagnosis: Spastic cerebral palsy with diplegia, hemiplegia, or quadraplegia.

Performance status: Gross Motor Function Classification Score levels II – IV as determined by the Gross Motor Function Measure-66 (see Appendix 1).

Autologous umbilical cord blood available at a private or public cord blood bank with a minimum total nucleated cell dose of ≥ 1 x 107 cells/kilogram.

Parental consent.

Exclusion Criteria:

Athetoid cerebral palsy.

Autism and autistic spectrum disorders without motor disability.

Hypsarrhythmia.

Intractable seizures causing epileptic encephalopathy.

Evidence of a progressive neurologic disease.

Known HIV or uncontrolled bacterial, fungal, or viral infections.

Impaired renal or liver function as determined by serum creatinine >1.5mg/dL and/or total bilirubin >1.3mg/dL.

Head circumference >3 standard deviations below the mean for age.

Known genetic disease or phenotypic evidence of a genetic disease on physical examination.

Concurrent genetic or acquired disease or comorbidity(ies) that could require a future allogeneic stem cell transplant.

Requires ventilatory support, including home ventilator, CPAP, BiPAP, or supplemental oxygen.

Patient’s medical condition does not permit safe travel.

Previously received any form of cellular therapy.

Autologous umbilical cord blood unit has any of the following:

Total nuclear cell dose < 1 x 107 cells/kilogram

Positive maternal infectious disease markers (except CMV)

Evidence of infectious contamination of the cord blood unit

Lack of a test sample to confirm identity

Evidence of a genetic disease

Unable to obtain parental consent.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01147653

Contacts

Locations

Sponsors and Collaborators

Duke University

Roberson Foundation (funding)

Investigators

More Information 
No publications provided

Keywords provided by Duke University:

Additional relevant MeSH terms:

ClinicalTrials.gov processed this record on October 22, 2010

http://www.clinicaltrials.gov/ct2/show/NCT01147653?term=duke+cord+blood

We apologize. We are temporarily down while we migrate the site to a new platform so we can make quicker updates to help keep the Lets Cure CP community up to date. In the meantime join us on Facebook to stay informed and this site should be back up shortly.