A new clinical trial that is probably one of the first of its kind will study two types of stem cell treatments for children who have cerebral palsy. The University of Texas Health Science Center at Houston (UTHealth) Medical School will host this trial.
This trial will be conducted in a blinded fashion and will test the efficacy of stem cells against a placebo. The types of stem cells investigated in this clinical trial include banked cord blood stem cells and bone marrow stem cells. Charles S. Cox Jr., M.D., professor of pediatric surgery at the UTHealth Medical School and director of the Pediatric Trauma Program at Children’s Memorial Hermann Hospital will lead this clinical trial, and Sean I. Savitz, M.D., chair of the UTHealth Department of Neurology will serve as the co-principal investigator.
This FDA-approved study builds on Dr. Cox’s previous work on traumatic brain injury and the use of stem cell therapy to treat it in children and adults. In particular, Cox has focuses on those patients who have been admitted to Children’s Memorial Hermann and Memorial Hermann-Texas Medical Center after having suffered a traumatic brain injury. Prior research by Cox and others have shown that stem cells derived from a patient’s own bone marrow can be used safely used in pediatric patients with traumatic brain injury. In this clinical trial, Cox is also studying cord blood stem cell treatment for these injuries in a separate clinical trial.
Cox’s trials will enroll a total of 30 children between the ages of 2 and 10 who have cerebral palsy. 15 of these subjects have will have their own cord blood banked at Cord Blood Registry (CBR), and 15 will not have banked any cord blood. In each of these groups, five subjects will be randomized to a placebo control group.
After treatment the children will be neurologically assessed at six, 12 and 24 months. None of the parents will be told if their child received stem cells or a placebo until the 12-month follow-up exam, and at this time, those parents whose children received the placebo may elect to have their child receive a stem cell treatment either by means of stem cells isolated from bone marrow harvest or with stem cells from cord blood banked with CBR.
Collaborators in the study include CBR, Let’s Cure CP, TIRR Foundation and Children’s Memorial Hermann Hospital.
A stroke results when the brain suffers from “ischemia” or a lack of blood flow for an extended period of time. Blockage in the small vessels that feed blood to the brain can cause a trans-ischemic attack (TIA) or stroke. The lack of oxygen causes localized death of brain cells. The dying cells dump a whole gaggle of molecules into the spaces surrounding nearby brain cells, and these cell-derived molecules can actually poison surrounding cells, thus increasing the area that dies as a result of a stroke.
New work from by Henry Ford Hospital researchers in Detroit, Michigan suggests that some of the molecules released by brain cells during a stroke might actually help the brain heal after a stroke. Small RNA molecules or microRNAs that are packaged into lipid-bound vesicles in cells known as exosomes are released by stem cells after a stroke and seem to contribute to neurological recovery.
Exosomes are secreted vesicles that were first discovered nearly 30 years ago. They were, at first, considered little more than garbage cans whose job was to discard unwanted cellular components. However, once cell biologists began to study these little structures, evidence began to accumulate that these dumpsters also act as messengers that convey information to distant tissues. Exosomes contain cell-specific payloads of proteins, lipids, and genetic material that are transported to other cells, where they alter function and physiology.
Therefore, it is little wonder that exosomes can also transport microRNAs. In this present study from the laboratory of Michael Chopp, rats were given experimentally induced strokes, and then the neurological recovery of the rats was examined at the molecular level.
Chopp and his colleagues first isolated mesenchymal stem cells (MSCs) from the bone marrow of their laboratory rats. Then they genetically engineered these MSCs to release exosomes laden with specific microRNAs; in particular miR-133b.
MicroRNAs are a class of post-transcriptional regulators. Since they are usually only about 22 base pairs in length, they are far too short to encode anything. microRNAs usually bind to complementary sequences in the 3’ untranslated region of messenger RNAs, and this binding silences the RNA, which simply means that the RNA cannot be recognized by ribosomes and will not be translated into protein, or that the RNA is degraded by special enzymes that target RNAs bound by microRNAs. Single microRNAs target hundreds genes at a time, and some 60% of all genes are regulated by microRNAs. MicroRNAs are abundantly present in all human cells. They are also highly conserved in organisms ranging from the unicellular algae Chlamydomonas reinhardtii to mitochondria in vertebrates, which suggest that they are a vital part of genetic regulation throughout the plant and animal kingdoms.
The microRNA known as miR-133b has been shown to enhance the death of prostate cancer cells when they are delivered to them (see Patron JP, Fendler A, Bild M, Jung U, Müller H, et al. (2012) MiR-133b Targets Antiapoptotic Genes and Enhances Death Receptor-Induced Apoptosis. PLoS ONE 7(4): e35345. doi:10.1371/journal.pone.0035345). However, because different cell types show different responses to the same reagents, exposing brain cells to this microRNA after a stroke might elicit a very different response.
By raising or lowering the amount of miR-133b in MSCs, Chopp and his colleagues were able to determine the effects of miR-133b on brains cells after a stroke. Chopp and others injected their genetically engineered MSCs into the bloodstream of rats 24 hours after inducing a stroke in these animals. When the exosomes of the MSCs were enriched in miR-133b, the neurological recovery in the rats was amplified, but when injected MSCs were deprived of miR-133b, the neurological recovery was substantially less.
To measure neurological recovery, researchers separated the disabled rats into several groups and injected each groups with saline, nongenetically-engineered MSCs, MSCs with low levels of miR-133b, and MSCs with high levels of miR-133b. The rats were given behavioral tests 3, 7, and 14 days after treatment. These tests measured the gait of the animals on a grid to determine if the rats could walk on an unevenly spaced grid (foot-fault test). The second test determined how long it took the rats to remove a piece of adhesive tape that was stuck to their front paws.
in every test, the rats injected with miR-133b-enriched MSCs showed superior levels of neurological recovery. Autopsies of these same animals revealed that the rats treated with miR-133b-enriched MSCs had enhanced rewiring of the brain and axonal outgrowth. In the areas of the brain adversely affected by the stroke, the rats showed increased axonal plasticity and neurite remodeling.
Most stroke victims recover some ability to use their hands and other body parts on a voluntary basis, but almost half of all stroke victims are left with some weakness on one side of their body and many are permanently disabled by the stroke.
No treatment presently exists for improving or restoring this lost motor function in stroke patients, mainly because of mysteries about how the brain and nerves repair themselves.
Chopp said, “This study may have solved one of these mysteries by showing how certain stem cells play a role in the brain’s ability to heal itself to differing degrees after stroke or other trauma. Chopp also serves as the scientific director of the Henry Ford Neuroscience Institute.