In the first (April) issue of this four-part series about regenerative medicine, we talked about the gold rush into stem cell territory, seen by venture capitalists, researchers, and clinicians to contain rich seams of untapped potential for providing significantly better medicine. In this issue, we provide specific examples of stem cell therapies under development and in clinical trials.

Broken Bone

A filler material made of bone marrow-derived mesenchymal adult stem cells and amniotic fluid fetal stem cells grown on a polymer scaffold was used to fill gaps in damaged bone in rats. The method produced significantly higher new bone volume and strength compared to scaffolds without cellular augmentation, though it did not do so consistently.

The researchers used fluorescent quantum dots (qdots) to monitor the success of the therapy, and found that the qdots diminished the therapeutic effect. They are now exploring alternative cell tracking methods, such as genetically modifying the stem cells to express fluorescent proteins. As well, they hope to manually reprogram the stem cells to differentiate into bone cells, instead of relying on natural reprogramming.

Others are applying these methods in attempts to create stem cell therapies for severe composite injuries to multiple tissues including bone, nerve, blood vessels, and muscle.

Incontinence

Implanting a patient’s own stem cells into the bladder muscle might cure urinary incontinence in adults. Stem cells are extracted by needle biopsy from thigh muscle, grown in the lab, then injected into the bladder muscle, where they repair damage and regenerate the muscle.

A small trial has been underway in the US for two years. One early participant, a mother of two large babies whose deliveries left her prone to incontinence when she sneezed or coughed with a full bladder, was cured after three months of the therapy. Two-thirds of the trial participants have seen greater than a 50 percent improvement in their condition.

The procedure could be FDA-approved in another three years, following larger trials.

ALS (Lou Gehrig’s Disease)

A two-year phase I (safety) clinical trial involving injecting fetal-derived neural stem cells into the spines of 12 patients with ALS is getting underway in Michigan. (Fetal stem cells are derived from organs of the fetus and not from embryos.) The patients will receive five to 10 stem cell injections in the lumbar area of the spinal cord. In rats with ALS, the therapy preserved the large motor neurons and muscle strength that normally die in patients with the disease.

Blindness

Despite much success in animal trials, human trials of stem cell therapies need to be proven safe and, ideally, tolerated by the immune system. But the immune system is inactive in the eyes and the nervous system so are better earlier candidates to get past the rejection barrier and on to efficacy testing.

Advanced Cell Technology (ACT) has developed treatment an experimental therapy using human embryonic stem cells to treat degenerative eye diseases. The therapy has proved both safe and effective in animal studies, and may begin early human trials in the next few months. If the FDA approves, it will be the second embryonic-stem-cell-based treatment to progress to human trials—the first, as we noted in the April issue, was Geron’s trial of a therapy to repair damaged spinal cords.

ACT uses ESCs because they tend to spontaneously differentiate into retinal pigment epithelium (RPE) cells that support the photoreceptors needed for vision. Age-related macular degeneration and other eye diseases destroy RPE and lead to loss of vision. But before tackling age-related macular degeneration, ACT will try its therapy first on patients with the rare Stargardt’s disease, in which the supporting tissue to which RPE cells must attach remains intact.

Leukemia

The umbilical cord is another source of stem cells, but there are not many stem cells per unit of cord blood. After cultivating stem/progenitor cells from cord blood in the lab, using an experimental method that has been under development for a decade, researchers had enough to infuse ten leukemia patients in a phase I (safety) clinical trial, resulting in successful and rapid engraftment. Unlike normal donor blood, cord blood cells do not need to be perfectly matched to the patient, making therapy accessible to more patients.

The method of cultivation involved partially reprogramming the cells using a protein engineered for the purpose. The method resulted in cord blood containing as many CD34+ multipotent hematopoietic stem cells (which can turn into any type of blood cell) as conventional transplant sources.

Seven of the ten trial patients were still alive as of January this year, with no evidence of disease and with sustained, complete donor engraftment. Further clinical trials and technological improvements are needed, the researchers admit, but the principle has been proved.

Vascular Reconstruction

A new technique announced in January turns human embryonic and pluripotent stem cells (ESCs and iPSCs) into virtually unlimited quantities of functional endothelial cells to line blood vessels and build capillaries. When injected into mice, the cells were quickly assimilated into the circulatory system and functioned alongside normal vasculature. The near-term hope is to inject these cells into humans to heal damaged organs and tissues. Longer term, the method could accelerate research into genetically inherited vascular diseases.

The researchers believe their general approach can be applied to research and clinical applications for other tissues besides the vasculature. The method has “serious potential as a treatment for a diverse array of diseases, especially cardiovascular disease, stroke and vascular complications of diabetes,” according to its lead researcher.

For example, the cells could be used to create blood vessels in engineered tissue or administered to patients directly to repair injury after heart attack or stroke, resupplying blood to damaged organs. “[Eventually], we want to be able to inject slurries of these cells into people who have suffered heart attacks, and allow those tissues to recuperate by renewed blood flow,” he said.

With the plentiful supply of endothelial cells that the new method provides, other researchers are creating biological scaffolds to model the microenvironment of the vasculature, which they can then use to test for functionality and longevity of treatments.

Human clinical trials are envisaged within the next five years.

Brain Damage & Stroke

It is becoming increasingly clear that stem cells don’t simply substitute for damaged cells. Rather, they appear to instruct other cells to carry out normal organ maintenance and initiate damage control. According to one researcher, this so-called “chaperone effect,” rather than the cell-replacement aspect of stem-cell-based regenerative medicine, may be the low-hanging fruit.. He likened the stem cells to “little doctors that went about “looking for the defect, … diagnosing it, and … differentiating into what’s needed to repair the defect.”

This hypothesis was supported by experiments in which stem cells were injected directly into the brains of mice whose mothers were given heroin during pregnancy. Most of the transplanted cells did not survive, yet neural birth defects in the mice were reversed. Before they died, however, the stem cells induced the brain’s own cells to carry out repairs, and the mice were able to function normally thereafter.

Transplanted stem cells have also shown promise in reversing brain damage caused by stroke, as well as by neurological diseases like Parkinson’s, Alzheimer’s, and Huntington’s. Mouse experiments also show that transplanted stem cells produce the same result regardless of whether they are administered intravenously or by direct injection into the brain, although some researchers have doubts about the intravenous approach.

Stroke 2

Neural stem cells grown on a biodegradable polymer and injected into stroke-damaged rats’ brains caused new nerve tissue to grow into the stroke-induced cavities and completely repair the brain damage within seven days. The key was the biodegradable polymer called PLGA, which not only gave the stem cells time to remain in the area of stroke damage and establish connections with surrounding brain tissue, but also left space for blood vessels and other tissues to form.

The researchers next plan to add the growth factor VEGF to encourage blood vessels to enter the new tissue and speed its development into mature tissue.

PLGA stimulates the growth and differentiation of neural stem cells at three different scales, which one researcher described thus: “At the large scale, it enables the void formed by the injury to get new blood vessels very quickly, which is vital if the new tissue is to survive. At the cellular level, the scaffold surface allows stem-cell receptors to attach to it. And at the molecular level, it will allow cells to mix with the right growth factors.”

While human trials of the stem cell/PLGA matrix for stroke victims is a long way off, the PLGA polymer itself will be marketed within 12 months for use in bone surgery.

Stroke 3

A 12-patient, two-year phase I (safety) trial of a direct-injection fetal stem cell therapy for stroke got underway last year, according to the BBC. The first group of three patients was given a low dose of two million stem cells. The dose will be gradually increased over the trial period and the final group will receive 20 million cells, which it is hoped might be enough to initiate regeneration in the damaged brains.

Reneuron, the company that developed the stem cells from an aborted fetus, was denied permission, by a conservative FDA, to begin trials in the US two years ago. The UK’s equivalent body, the Medicines and Healthcare Products Regulatory Agency, took a more positive view.

Anti-abortion activists claimed the use of fetal stem cells was unethical. The lead researcher responded: “We have only taken one donation of tissue to make this product. We have a technology that is able to scale up an individual cell into all of the cells that are required to treat thousands of patients. We think this is a major plus in the technology we have and really negates the ethical concerns about the original use of foetal tissue. It would be ethically wrong to deny treatment.”

Spinal Cord Injuries

Twenty patients paralyzed below the level of their severe chronic spinal cord injuries received a treatment combination of partial scar removal, transplantation of nasal tissue containing stem-like olfactory mucosal cells, and intense rehabilitation. The injuries in the study patients were 18 months to 15 years old. The patients, ages 19 to 37, had no use of their legs before the treatment. One paraplegic treated almost three years after the injury now ambulates with two crutches and knee braces. Ten other patients ambulate with physical assistance and walkers (with and without braces). One 31-year-old male tetriplegic patient uses a walker without the help of knee braces or physical assistance.

Although they are not true stem cells, olfactory mucosal cells appear to be very immature and capable of differentiating into a variety of cell types.

The researchers hope to conduct a larger clinical trial.

[Disclosure: The Detroit Medical Center is involved in this research.]

Multiple Sclerosis

Early last year, results of a three-year phase I study suggested that a stem cell therapy (autologous non-myeloablative hemopoietic stem-cell transplantation) that had generally failed in trials to help  patients at an advanced (“secondary-progressive”) stage of multiple sclerosis would work in patients at an earlier (“relapsing-remitting”) stage of the disease.

The disease was halted from further progression in all 21 patients and 17 of them improved by at least one point on a neurological disability scale. This was the first time any treatment reversed some of the damage caused by the disease. Five patients eventually relapsed, but went into remission after receiving other therapy.

A stage II randomized controlled trial in a larger number of patients is underway to compare the treatment with standard therapy.

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To us, that seems a pretty impressive lineup of therapies that just a few years ago would have seemed impossible. Imagine where we will be in five and ten years’ time, as some of them come to market and as others, fed by further understanding and advances in stem cell research, come to trial.

Here are some examples of recent advances that did not make it into last month’s issue:

Adult Cells Transformed Without IPS Stage

If creating iPSCs is such a bother, wouldn’t it be nice if we didn’t have to? Well, it seems we don’t have to. Scientists have turned mouse skin cells directly into nerve cells, with the application of just three genes. The neurons are fully functional, able to do “all the principal things that neurons in the brain do,” including connecting with and signaling to other nerve cells. The transformation took a week (iPSC production can take several weeks) and was almost 20 percent efficient (iPSC production is usually only 1-3 percent efficient.) The three genes were winnowed down from a pool of 19 candidate genes.

Because the neurons can show complex, appropriate behaviors like generating electrical currents and forming synapses, they provide a new model for studying brain cell function in neurodegenerative diseases such as Parkinson’s or Alzheimer’s or heritable mental diseases. Neurons can quickly be made from patients suffering from those diseases.

The researchers are now trying to get human cells to perform the same feat.

Another “Ethical” Stem Cell Method

The common method to make iPSCs is to deliver the genes that reprogram (“de-differentiate”) the cell using a virus (or “viral vector,” as scientists are wont to call it.) In January last year, a British team announced they had managed to create iPSCs without using a virus to deliver the reprogramming genes. In March, a Canadian team announced they had achieved the same thing.

Magnetized Stem Cell Therapy Delivery

Stem cells coated with magnetic nanoparticles routinely used in MRI scans and injected into the blood stream could be guided by doctors to any location where they might be needed. In rat trials, the magnetic targeting led to a five-fold increase in cell localization at a site of vascular injury. Human trials could begin within the next few years. The technique could be especially useful inside blood vessels where the blood is flowing fast and therapeutic cells might get swept past the damage site before getting a chance to do their work.

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Stem cell therapies are pretty amazing, but next month, in the third of this four-part series on regenerative medicine, we will look at an even more extraordinary potential form of regenerative medicine: Regeneration itself, as practiced by salamanders and—believe it or not—human fetuses.

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