Tiny, Poorly-Controlled Study Shows No Benefit for Stem Cell Treatment in Children with Optic Nerve Hypoplasia


Optic nerve hypoplasia (ONH), an underdevelopment of optic nerves that occurs during fetal development, can appear as an isolated condition or as a part of a group of disorders characterized by brain anomalies, developmental delay, and endocrine abnormalities. ONH is a leading cause of blindness in children in North America and Europe and is the only cause of childhood blindness that shows increasing prevalence. No treatments have been shown to improve vision in these children.

RetinaRetina ONH

Because stem cells heal or even regenerate some tissues, some have considered stem cell treatments as an option for this condition.  However, a very small clinical study at Children’s Hospital Los Angeles found no evidence that stem cell therapies improve vision for children with optic nerve hypoplasia (ONH). Their results are reported in the Journal of the American Association for Pediatric Ophthalmology and Strabismus (AAPOS).

Families with a child that has ONH are traveling to China to undergo stem cell treatments that would be illegal in the United States. Because there are presently no viable treatment options available to improve vision in ONH children, such trips are often an act of desperation. The American Association for Pediatric Ophthalmology and Strabismus has also expressed its concern about these procedures, which are usually rather expensive, and have a dubious safety record.

Pediatric neuro-ophthalmologist Mark Borchert, MD, director of both the Eye Birth Defects and Eye Technology Institutes in The Vision Center at Children’s Hospital Los Angeles, realized that a controlled trial of sufficient size was needed to evaluate whether stem cell therapy is effective as a treatment for children with ONH. He agreed to conduct an independent study at the behest of Beike Biotech, which is based in Shenzhen, China and offers a stem cell treatment for ONH. This treatment uses donor umbilical cord stem cells and injects these cells into the cerebrospinal fluid.

Beike Biotech identified 10 children with bilateral ONH (ages 7 to 17 years) who had volunteered to travel to China for stem cell therapy. These patients gave their consent to participate in the study and Children’s Hospital found matched controls from their clinic. However, only two case-controlled pairs were evaluated because Beike Biotech was only able to recruit two patients.

Treatments consisted of six infusions over a 16-day period of umbilical cord-derived mesenchymal stem cells and daily infusions of growth factors. Visual acuity, optic nerve size, and sensitivity to light were to be evaluated one month before stem cell therapy and three and nine months after treatment.

Unfortunately no therapeutic effect was found in the two case-control pairs that were enrolled. “The results of this study show that children greater than 7 years of age with ONH may have spontaneous improvement in vision from one examination to the next. This improvement occurs equally in children regardless of whether or not they received treatment. Other aspects of the eye examination included pupil responses to light and optic nerve size; these did not change following treatment. The results of this research do not support the use of stem cells in the treatment of ONH at this time,” said lead author Cassandra Fink, MPH, program administrator at The Vision Center, Children’s Hospital Los Angeles.

However, confounding factors affect the interpretation of these results because the test subjects received additional alternative therapies (acupuncture, functional electrical stimulation and exercise) while receiving stem cell treatments. They were not supposed to receive such treatments. Additionally, the investigators could not determine the effect of these additional therapies on the subjects’ eyes.

“This study underscores the importance of scientifically testing these procedures to validate them and ensure their safety. Parents of afflicted children should be aware that the science behind the use of stem cell technology is unclear. This study takes a step toward testing this technology and finds no beneficial effect,” said William V. Good, MD, senior associate editor, Journal of AAPOS and Clinical Professor of Ophthalmology and Senior Scientist at the Smith-Kettlewell Eye Research Institute.

Basically, we have an incredibly small study that is also poorly controlled. Because the optic nerve forms during embryonic, fetal and postnatal development, using stem cells to make new nerves seems like a long shot as a treatment.  I better treatment strategy might be to increase the myelination of the optic nerve with neural stem cells, oligodendrocyte precursor cells (OPCs), or Schwann cells.  In general, this study does little to establish the lack of efficacy of such a stem cell treatment.

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Faulty Stem Cell Regulation Contributes to Down Syndrome Deficits


People who have three copies of chromosome 21 have a genetic condition known as Down Syndrome (DS). In particular, patients who have an extra copy of a small portion of chromosome 21 (q22.13–q22.2) known as the Down Syndrome Critical Region or DSCR have the symptoms of DS. The DSCR contains at least 30 genes or so and some of them tightly correlate to the pathology of DS. For example, the APP (amyloid protein precursor) gene accounts for the accumulation of amyloid protein in the brains of DS patients. DS patients develop Alzheimer disease-like pathology by the fourth decade of life, and the APP protein is overexpressed in the adult Down syndrome brain. Another gene found in the DSCR called DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) encodes a member of the dual-specificity tyrosine phosphorylation-regulated kinase family and this protein participates in various cellular processes. Overproduction of DYRK1A seems to cause the abnormal brain development observed in DS babies.

Another gene found in the DSCR is called USP16 and this gene encodes a protein that removes small peptides called ubiquitin from other proteins. Ubiquitin attachment marks a protein for degradation, but it can also mark a protein to do a specific job. USP16 removes ubiquitin an either stops the protein from acting or prevents the proteins from being degraded. Overexpression of UPS16 occurs in DS patients, and too much UPS16 protein affects stem cell function.

Michael Clarke, professor of cancer biology at the Stanford University School of Medicine, said, “There appear to be defects in the stem cells in all the tissues we tested, including the brain.” Clarke continued, “We believe USP16 overexpression is a major contributor to the neurological deficits seen in Down Syndrome.” Clarke’s laboratory conducted their experiments in mouse and human cells.

Additional work by Clarke and his colleagues showed that downregulation of USP16 partially rescues the stem cell proliferation defects found in DS patients.

Clarke’s study suggests that drugs that reduce the activity of USP16 could reduce the some of the most profound deficits in DS patients.

This paper also details some of the pathological mechanisms of DS. DS patients age faster and exhibit early Alzheimer’s disease. The reason for this seems to rely on the overexpression of UPS16, which accelerates the rate at which stem cells are used during early development. This accelerated rate of stem cell use burns out and exhausts the stem cell reserves and, consequently, the brains age faster and are susceptible to the early onset of neurodegenerative diseases.

After examining laboratory mice that had a rodent form of DS, Clarke and his coworkers turned their attention to USP16 overexpression in human cells. Clarke collaborated with a Stanford University neurosurgeon named Samuel Cheshier and their study showed that skin cells from normal volunteers grew much more slowly when the Usp16 gene was overexpressed. Furthermore, neural stem cells, which normally clump into little balls of cells called neurospheres, no longer formed these structures when Usp16 was overexpressed in them.

a, Proliferation analysis, as well as SA-βgal and p16Ink4a staining, of three control and four Down’s syndrome (DS) human fibroblast cultures show growth impairment and senescence of Down’s syndrome cells. b, c, Lentiviral-induced overexpression of USP16 decreases the proliferation of two different control fibroblast lines (b), whereas downregulation of USP16 in Down’s syndrome fibroblasts promotes proliferation (c). d, Overexpression of USP16 reduces the formation of neurospheres derived from human adult SVZ cells. The right panel quantifies the number of spheres in the first and second passages. P < 0.0001. All the experiments were replicated at least twice. Luc, luciferase.
a, Proliferation analysis, as well as SA-βgal and p16Ink4a staining, of three control and four Down’s syndrome (DS) human fibroblast cultures show growth impairment and senescence of Down’s syndrome cells. b, c, Lentiviral-induced overexpression of USP16 decreases the proliferation of two different control fibroblast lines (b), whereas downregulation of USP16 in Down’s syndrome fibroblasts promotes proliferation (c). d, Overexpression of USP16 reduces the formation of neurospheres derived from human adult SVZ cells. The right panel quantifies the number of spheres in the first and second passages. P < 0.0001. All the experiments were replicated at least twice. Luc, luciferase.

Conversely, when cultured cells from DS patients had their USP16 activity levels knocked down, their proliferation defects disappeared. In Clarke’s words, “This gene is clearly regulating processes that are central to aging in mice and humans, and stem cells are severely compromised. Reducing Usp16 expression gives an unambiguous rescue at the stem cell level. The fact that it’s also involved in this human disorder highlights how critical stem cells are to our well-being.”