Sam Maddox: The mid-year Stem Cell Report

The mid-year Stem Cell Report by Sam Maddox.

Mid-year Stem Cell Report
Posted by Sam Maddox
Friday, June 22, 2012
Geron’s out of the picture now, having quit its embryonic stem cell safety trial for acute spinal cord injury last fall after enrolling just five patients. No official reports but four of the five who got the cells have more or less gone public: no harm. No significant gain, either. The company is moving ahead with trials of imetelstat, a maintenance drug for advanced lung cancer.

Meanwhile, stem cell clinical research for spinal cord trauma continues on several fronts. Our collective minds’ eye may think of stem cells as replacements for broken ones in the spinal cord. Most scientists I’ve talked to think stem cells will be more useful as chemical conditioners and stabilizers, not spare parts.

Here is a mid-year update.

California-based StemCells,. Inc. is still enrolling people three to 12 months post-injury, in Switzerland, to test purified human neural stem cells for safety and preliminary efficacy.

The company reports that is has dosed the first three patients all classified as ASIA A (no neurological function below the injury level). The second and third groups will be B and C, classifications, meaning less severe injuries. Not much news. Says the company:

All patients enrolled were transplanted with a dose of 20 million cells at the site of injury in the thoracic spinal cord. There were no abnormal clinical, electrophysiological or radiological responses to the cells, and all the patients were neurologically stable through the first four months following transplantation of the cells.  Changes in sensitivity to touch were observed in two of the patients.

Mechanism? Aileen Anderson, a scientist at UC Irvine whose preclinical work (the animals got good recovery) underpins the trial, noted in an earlier publication that “…following both sub-acute and early chronic transplantation we have shown that the predominant [stem cell] differentiation is oligodendroglial and survival of [stem cells] is required to sustain locomotor recovery, suggesting that oligodendrocytes integration with the host is likely a key mechanism of recovery.”

StemCells recently announced a Phase I/II clinical trial of the company’s human neural stem cell line for dry age-related macular degeneration. at the Retina Foundation of the Southwest’s Anderson Vision Research Center in Dallas.

Speaking of low vision, the only remaining embryonic stem cell trials listed on clincaltrials.gov are for macular degeneration  and Staargards macular dystrophy. These are being conducted by Advanced Cell Technology, a California company, at UCLA and the Oregon Health and Sciences University in Portland. The company published preliminary data earlier this year. No bad news, and that’s good news. From the company:

Although there is little agreement between investigators on visual endpoints in patients with low vision, it is encouraging that during the observation period neither patient lost vision. Best corrected visual acuity improved from hand motions to 20/800 (and improved from 0 to 5 letters on the Early Treatment Diabetic Retinopathy Study [ETDRS] visual acuity chart) in the study eye of the patient with Stargardt’s macular dystrophy, and vision also seemed to improve in the patient with dry age-related macular degeneration (from 21 ETDRS letters to 28).

Maryland-based Neuralstem continues its Phase I trials for spinal cord-derived neural stem cell transplants in people with ALS, at Emory University Hospital in Atlanta, Georgia. So far 16 patients have gotten the adult stem cells; one got two doses, in both upper and lower regions of the spinal cord. No reports of benefits (none anticipated) and no reports of adverse side effects.
Why this would be of interest to spinal cord injury community: It’s dealing with chronic, stable neurological damage.

CIRM: The California Institute for Regenerative Medicine (CIRM) continues to fund potential stem cell treatments. CIRM had fronted $25 million in the failed Geron trial (it was refunded) and there are many diseases being addressed in many projects. Here’s one related to SCI:

Zhigang He is the scientist who found a way to adjust the genetic programming of axons to permit them to grow in ways not seen before. By deleting the PTEN gene, axons of the cortical spinal cord moved well past the injury site. But the research is still figuring this out. So far, they don’t yet know how to make the regenerated axons functional, nor do they know how to dial down the gene in an animal that has already been injured. CIRM funded He’s group $5,609,890 to see if stem cells might be part of the solution.:

We recently made breakthrough discoveries in identifying key biological mechanisms stimulating the re-growth of injured axons in the adult nervous system, which led to unprecedented extents of axon regeneration in various CNS injury models. While our success was compelling, we found that many regenerated axons were stalled at the lesion sites by the injury-induced glial scars. Furthermore, it is unclear whether the regenerated axons can form functional synaptic connections when they grow into the denervated spinal cord. This proposed research program is aimed at solving these obstacles by using human stem cell technologies. In the first aim, we will use human neural stem cells to engineer “permissive cell bridges” that can guide the maximum number of regenerating axons to grow across injury sites. In the second aim, we will test the therapeutic potential of human stem cell-derived neurons in forming “functional relays” that could propagate the brain-derived signals carried by regenerating axons to the injured spinal cord. Together, our research program is expected to develop a set of therapeutic strategies that have immediate clinical implications for human SCI patients.

Recently published clinical results, from Korea: “Long-term Results of Spinal Cord Injury Therapy Using Mesenchymal Stem Cells (MSC) Derived From Bone Marrow in Humans.”
This group thinks MSCs may diminishing glial scars in human spinal cords, thus making regeneration easier. Too early to tell but this trial enrolled 10 people. Three, all cervical ASIA B injuries (some function below lesion) “showed continuous and gradual motor improvement in the upper extremities and significant MRI and electrophysiological changes during long-term follow-up.”

ReNeuron is a UK biotech that has transplanted neural stem cells into the brains of people who had ischemic strokes. From the company:

No cell-related adverse events or adverse immune-related responses were reported in any of the patients treated to date. A number of the patients experienced minor procedure-related adverse events such as asymptomatic bleeds or superficial scalp infections at the implantation wound site….Reductions in neurological impairment and spasticity were observed in all [five] patients compared with their stable pre-treatment baseline performance and these improvements were sustained in longer term follow-up.

NEJM: “Clinical Implications of Basic Research: Stem Cells and Spinal Cord Repair,” a recent article in the New England Journal of Medicine by physician scientists Evan Snyder, from Sanford–Burnham Medical Research Institute, La Jolla, CA, and Yang Teng, Harvard Medical School.

Their goal was to coach clinicians on how challenging SCI research really is, especially for chronic SCI, characterized as the “third rail of neurorepair.” Here’s the set up:

For the past couple of decades, clinicians have watched the stem-cell field with a mixture of anticipation and skepticism. No group of patients has been more expectant than those with spinal cord injuries. Therapies for spinal cord injury have been promised almost since the dawning of the stem-cell field. The recent launch — and abrupt termination — of a phase 1 clinical trial for acute spinal cord injury by the biotechnology company Geron whetted the appetite, and then fueled the frustration, of these patients.

Snyder and Teng are hopeful, and believe transplanted stem cells can be coaxed to fulfill “their fundamental teleologic role of maintaining homeostasis in a perturbed system.” The stem cell, they note, might be the “glue” that bonds many multidisciplinary approaches to spinal cord repair. They lay out a short case that rigorous science is still needed to safely move from lab to clinic, and they cite one recent set of stem cell studies as an example: stem cells from dental pulp (readily accessible from a living patient and immunologically matched) and reported recovery of function in animal models. The work comes from Japan, “Human Dental Pulp-Derived Stem Cells Promote Locomotor Recovery After Complete Transection of the Rat Spinal Cord by Multiple Neuro-regenerative Mechanisms.”

The study showed that human dental pulp (from baby teeth or adult third molars) improved rat SCI recovery three ways: preserving nerves and myelin; blocking inhibitory factors near the injury; and replacing lost cells. Said the authors, the dental pulp story highlights “that spinal cord injury is not a monolithic entity but rather a series of concurrent and interacting pathological processes; that multimodal actions will be required to combat the various facets of this malady…”

Snyder and Teng recapitulate what makes it so hard, and these are the take home lessons about current stem cell science:

The cascade of pathological processes that characterize spinal cord injury unfolds in the context of a neuroanatomy that is complex, with connections and functions that have been rendered regionally discrete within a span of millimeters, if not microns, during a finely tuned process that is part of embryonic development.

….Substantial degrees of spontaneous recovery that are not related to treatment can occur for reasons not entirely known or controllable.

…The field itself is inherently vulnerable to observer bias because it lacks adequate varieties of truly objective, quantifiable, discrete measures of spinal function attributable purely to single pathways. Other confounders include related maladies (e.g., pain, bladder and bowel dysfunction, muscle atrophy, osteopenia, skin breakdown, and fatigue); the unmonitored effects of learning, environmental stimulation, motivation, and rehabilitation; the effect of immunosuppressant drugs or use of experimental animals with immunodeficiency; the sex and strain of experimental animals; and in stem-cell transplantation, the fusion of donor cells with host cells, leading to the mistaken identification of a host cell as having come from the graft.

…In addition, the field is plagued by an incomplete knowledge of the relative contributions of the multiple pathological events that unfold after trauma and thus is poorly guided as to which processes should be combated in order to restore or preserve function. Although it is clear that the crux of spinal cord injury is the interruption of cortical involvement in spinal-mediated processes through ascending sensory and descending motor connections, it is far more daunting to re-create circuitry than to preserve the intricate connections established during embryonic development.

http://www.spinalcordinjury-paralysi…em-cell-report

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