Stem Cell Treatment Studies for Nuerological Disorders

[SorcererXIII]

What follows is a large dump of research studies of stem cell treatments on various neurological disorders (my 10 month old son has Kernicterus, which is kind of like CP or a stroke, hence that was my focus). My initial intent here was to determine if there is any empirical difference in efficacy between Adipose, Bone Marrow, Umbilical Cord, and Neuron-like stem cells in healing nervous system damage.

But...there are just so many of them. The ones below are not necessarily the best, just the ones that caught my eye. In each one there are references to dozens more. Some are on humans, some are on animals. I did my best to put a summary of each study. I was trying to get an idea of how many stem cells are used, what type, what markers, etc. I think did about as well as you could expect from someone with no medical background. Any doctors here are welcome to comment with clarifications.

As I accumulated these, I didn't find any that indicated that the treatments are dangerous or do anything but help. I couldn't help but wonder about all those media articles about how stem cell treatments are "unproven" and how terrible it is that doctors outside the US are able to offer them free of restriction. I'm no medical professional, but it looks to me like there is just gobs and gobs of proof.



Adipose Stem Cells

Efficacy of Human Adipose Tissue-Derived Stem Cells on Neonatal Bilirubin Encephalopathy in Rats
https://www.researchgate.net/publication/292154720_Efficacy_of_Human_Adipose_Tissue-Derived_Stem_Cells_on_Neonatal_Bilirubin_Encephalopathy_in_Rats

• 6 Rats given kernicterus. 3 rats given 10^5 hADSCs intrathecally, 3 given placebo
• Treated rats performed significantly better in Akynesia, Bradykinesia, TUNEL apoptosis, test, slip test, and ABR
• Florescence microscopy used to confirm homing of the hADSCs to the basal ganglia and cerebellum
• hADSCs shown to efficiently decrease apoptis by supplying the appropriate neurological environment at site of the injury
• Caveats: Rats given kernicterus on day 9, treated on day 10 - so effects may be neuroprotective rather than regenerative. Optimal time of transplantation said to be 1 week after injury (http://www.ncbi.nlm.nih.gov/pubmed/21375803)

Comparison of human adipose-derived stem cells and chondroitinase ABC transplantation on locomotor recovery in the contusion model of spinal cord injury in rats.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322153/

• 6 rats given 1x10^6 hADSCs through intraspinal injection
• 6 rats given Chondroitinase ABC through intraspinal inejection
• 6 rats for control
• hADSCs and ChABC both found to significantly promote locomotor function (BBB score) by 8 weeks.
• hADSCs don’t differentiate into neurons, but secrete Cytokines such as interleukins, stem cell factor, NGF, BDNF, that may result in Glial cell proliferation and additional axonal growth
• Cells high in CD44, CD73, CD90; CD31 and CD45 only in 0.55% and 1.32% of cells
• ChABC degrades glial scar, reduces glial fivrillary acidic protein, increases protein-43, redues extent of necrotic area, overal countering the Neuro-inhibitory environment
• Also cavity size of contusion reduced for treated rats

Bone Marrow Stem Cells

Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: a preliminary clinical study.
http://www.ncbi.nlm.nih.gov/pubmed/24100132

• 52 patients with CP received bone marrow derived mesenchymal stromal cells (BM-MSC)
• P1 Patients >= 5 years (n=27) had 2 intrathecal transplantations, 1 intra-parenchymal (injected using stereotactic surgery)
• P2 Patients <= 5 years (n=19) had 4 intrathecal transplantations.
• Each injection consisted of 2 x 10^7 cells
• GMFM-88 Total score measured as 0-100% divided into 5 groups (A-lying+rolling, B-Sitting, C-Crawling, D-Standing, E-Walking), each 0-100%, GMFM-66 is update version of this
• GMFM-66 reference scores used as control (https://canchild.ca/system/tenon/assets/attachments/000/000/222/original/tabulated_gmfm66_percentiles.pdf)
• Total GMFM-88 increased by 10 at 18 months, GMFM-66 increased by 6.5 after 18 months
• GMFM-66 percentile ranking (i.e. corrected for age improvements) increased by 10 at 6 months, 12 after 18 months
• Surprisingly no significant difference between P1 and P2 (brain injection vs lumbar puncture), but hypothesized this could be due to age
• More than half made progress as early as 2 or 3 days after the first lumbar puncture

Clinical Outcomes of Transplanted Modified Bone Marrow–Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study
http://stroke.ahajournals.org/content/early/2016/06/02/STROKEAHA.116.012995.abstract

• Modified allogeneic bone marrow mesenchymal stem cells (SB623) injected into brains of 18 stroke victims
• 6 patients had substantial (“stunning”) levels of improvement
• Mean increase 6.88 increase in european stroke scale, decrease 2.0 in national institutes of health stroke scale, 19.20 increase in Fugl-Meyer total score

Treatment of one case of cerebral palsy combined with posterior visual pathway injury using autologous bone marrow mesenchymal stem cells
http://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-10-100

• 11 year old boy given 4 infusions of intravenous autologous BMSCs, 4x10^7 cells each
• 1 year after, Visual accuity increased from 30cm/20cm to 100cm/80cm, right lower limb muscle tensions decreased, patient walked more smoothly
• Cells high in CD44, CD29, CD54, and CD106; negative for CD45, CD34, HLA-DR, CD14
• Thought that BMSCs found to express NGF and BDNF growth factors when cultured to the 6th generation. Also may induce angiogenesis, improving circulation.
• Healing continued 1 year after

Long-term recovery after bone marrow stromal cell treatment of traumatic brain injury in rats
http://thejns.org/doi/abs/10.3171/jns.2006.104.2.272

• 40 Wistar rats injured with cortical impact, 1 week later injected intravenously with 2x10^6, 4x10^6, or 8x10^6 BMSCs.
• 3 months later, BMSCs found in injured brain around the lesion (the 4x10^6 and greater doses yielded significantly larger amounts)
• Functional outcome improved in rats with 4x10^6 BMSCs or more.
• All doses found increased expression of BDNF but not NGF

Intravenous Administration of Human Bone Marrow Stromal Cells Induces Angiogenesis in the Ischemic Boundary Zone After Stroke in Rats
http://circres.ahajournals.org/content/92/6/692

• 1x10^ hBMSCs intravenously injected into 12 rats 24 hours after stroke.
• Found significant increases in vessesl/capillaries at boundary of lesions versus control rats
• Raised rat VEGF levels from 10.5 to 17.5 ng/ml

Protective effects of bone marrow stromal cell transplantation in injured rodent brain: Synthesis of neurotrophic factors
http://onlinelibrary.wiley.com/doi/10.1002/jnr.20494/abstract

• In vitro studies detected BMSC synthesis of NGF, BDNF, GDNF, and NT-3 growth factors.
• After intraventicular injection in mice, NGF levels significantly increased in cerebrospinal fluid

Intrathecal injection of CD133-positive enriched bone marrow progenitor cells in children with cerebral palsy: feasibility and safety
http://www.celltherapyjournal.org/article/S1465-3249(14)00830-5/abstract

• 12 children intrathecally injected with CD133+ cells enrliched from BM.
• GMFM-66, GMFCS, UK FIM+FAM, Ashworth Scale, and BBS outcomes all showed significant improvement
• Abstract does not explain how much of an improvement

Intrathecal Autologous Bone Marrow Derived MSC Therapy in Cerebral Palsy: Safety and Short Term Efficacy
http://article.sciencepublishinggroup.com/pdf/10.11648.j.bio.s.2015030401.14.pdf

• 44 cp patients injected intrathecally with 2x10^6 BM MSC
• Cells high in CD44, CD90, CD105, CD271, negative for CD45
• GMFCS ranking Improvements seen in 8/44 patients (from V to III, etc.)

Umbilical Cord Stem Cells

Umbilical Cord Blood Therapy Potentiated with Erythropoietin for Children with Cerebral Palsy: A Double-blind, Randomized, Placebo-Controlled Trial
http://onlinelibrary.wiley.com/doi/10.1002/stem.1304/full

• 31 CP Children given 3x10^7 UCB matched for 4/6 HLA markers + rhEPO, 33 given rhEPO only, 32 for control
• UCB group had significantly higher GMPM (14.5 vs 9.2) and BSID-II Mental (17.6 vs 11.5) and Motor (11.7 vs 5.6) scales at 6 months
• Younger than 36 months old UCB and rhEPO groups had higher GMFM gains than control (3.9 and 4.3 vs 1.2); older than 36 months did not

Intraspinal transplantation of CD34+ human umbilical cord blood cells after spinal cord hemisection injury improves functional recovery in adult rats
http://www.ncbi.nlm.nih.gov/pubmed/15129757/

• 20 rats given intraspinal 5x10^5 CD34+ Cord blood cells, 20 given 5x10^5 BMS cells, 20 given placebo.
• CD34+ rats achieved better Tarlov scores than BMS rats at day 17 and 14.
• Test went 28 days but no mention of results for this in abstract

The Levels of Pro-Inflammatory Factors Are Significantly Decreased in Cerebral Palsy Patients Following an Allogeneic Umbilical Cord Blood Cell Transplant
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3840980/

• Allogeneic (n=3) and Autologous (n=4) huCBs were intravenously injected into CP patients.
• Allogeneic treatment group had significantly decreased levels of pro-inflammatory factors and showed a statistically significant improvement in motor and social behavior vs. autologous group
• 4.25 x 10^7 HLA2 mismatched blood graft for autologous or 6.39 x 10^7 cells for allogeneic group.
• GMFM increased by 3 for allogeneic, 2 for autologous; GMPM 8 for allo, 6.5 for auto
• Hypothesis is that since autologous cord blood is from cp patients, it has higher inflammatory factors

Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy
http://download.springer.com/static/pdf/527/art%3A10.1186%2F1479-5876-10-58.pdf

• 20 CP patients treated intravenously with autologous cord blood (5.5 x 10^7/kg)
• 14/20 had increased stores, only 5 showed more improvement than expected; no scores published, but looked to average around 20 GMFM at 6 months based on graph

Intravenous versus intrastriatal cord blood administration in a rodent model of stroke.
http://www.ncbi.nlm.nih.gov/pubmed/12868063?dopt=Abstract

• Behavioral recover similar with both striatium and femoral vein hUCB delivery.
• Step test only showed improvements for femoral delivery

Effect of umbilical cord mesenchymal stromal cells on motor functions of identical twins with cerebral palsy: pilot study on the correlation of efficacy and hereditary factors
http://www.celltherapyjournal.org/article/S1465-3249(14)00800-7/abstract

• 8 pairs of identical twins received allogeneic UCMSC
• GMFM increase was significant, but not FMFM.
• Motor function increase was similar between twins but not between pairs, suggesting hereditary factors contribute to efficacy

Neural Stem Cells

Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563497/

• 30 CP patients received 1 x 10^7 NSC-like cells in the subarachnoid cavity, versus 30 control
• BMSCs high in CD29 and CD44 treated with FGF basic and retinoic acid to transform them to NSC-like cells
• Patients had Gross Motor Function Classification System (GMFCS) levels III-V; level IV and V showed most improvement
• Gross Motor Function Measure (GMFM-88) scores improved by 58.6 points (this seems to be on the 0-500 scale rather than 0-100, so, 11.72%?)
• No increase in language function (hypothesized because the patients were too old to benefit)

Effects of Neural Progenitor Cell Transplantation in Children With Severe Cerebral Palsy
http://ianr.org.cn/pdf/Effects of Neural Progenitor Cell Transplantation in Children With Severe Cerebral Palsy.pdf

• 45 cp patients injected with neural progenitor cells (NPCs) from aborted fetal tissue into the lateral ventricle
• Total GMFM increased by 9.2 after 6 months, total PDMS-FM by 17.58

 

[barbara]

You are doing an admirable job of research!

You do need to scrutinize who is blowing the "unproven" horn. In almost all cases, you will find a conflict of interest (aka money) that is behind the dire warnings. There is certainly enough evidence for me about the safety of adult stem cells, but the naysayers will never be satisfied because there is simply no profit for them if such treatments are administered by doctors as a practice of medicine.