The ultimate goal of human stem cell research has always been to harness the potential power of these cells to treat and cure intractable diseases. 

By transplanting millions of healthy stem cells into patients with a specific defect — be it paralysis, multiple sclerosis, ALS or others that are crippling and devastating — clinicians expect these pluripotent cells to develop into normal mature cells and take over critical functions of damaged tissue.

An accelerating research pace has prepared the way for the first stages of clinical trials, and UC scientists have paved the way to some of the first tests of stem cell therapies.

In 2009, a treatment developed by UC Irvine neuroscientist Hans Keirstead became the world’s first human embryonic stem cell therapy approved by the FDA for early-stage clinical trials. The treatment, now being carried out by Geron Corp., is designed to lessen the impact of severe spinal cord injuries by replacing lost myelin, the substance that normally insulates nerve cells and promotes communication between them.

In preliminary research with embryonic stem cells, the scientists were able to derive cells that could develop into healthy myelin-producing cells. Injected into animals, these cells went on to produce functioning myelin, allowing electrical conduction to resume in the nerves and enabling injured animals to walk again.

With this aim, three patients with severe spinal cord damage have been injected with human embryonic stem cells. If successful, the procedure will restore the communication between neurons, and thereby restore their ability to walk and move normally.

The early human trials test the safety of the procedure. The patient treatments began in October 2010. No adverse signs have been reported.

“Things are looking good,” Kierstead reports.

Treating a severe childhood disorder

Defective myelination of nerves also is observed in multiple sclerosis, cerebral palsy and a rare and fatal brain disorder called Pelizaeus-Merzbacher disease (PMD). This disorder is caused by a defective gene on the X chromosome that boys inherit from their mothers. Children affected with the severe form of PMD can’t walk or talk, and often die between ages 5 and 7.

Clinical trials were approved in 2009 for a stem cell therapy to treat PMD. This trial uses adult rather than embryonic stem cells. Both types have the remarkable ability to develop into many different cell types in the body. While embryonic stem cells are thought to be capable of specializing into any type of cell, adult stem cells are more limited — mainly able to differentiate into cell types from the tissue they are drawn from. But because of their more focused specialization, they may be less likely to be rejected after transplantation.

“This (PMD) is a tragic disease, and I think the families are aware that these early trials may not help their children,” said UCSF physician-scientist David Rowitch (in photo above). “But they recognize that it might help other children, and they’re very dedicated. I’m so impressed by how involved and engaged the families are in supporting the trials.”

“These early clinical trials are aimed at determining the safety of the stem cells being tested, a critical first step toward developing any effective therapy,” said Arnold Kriegstein, director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF.

In PMD, as in spinal cord injury, specialized cells called oligodendrocytes fail to make myelin. Rowitch and colleagues are collaborating with StemCells, Inc. in a clinical trial, testing the safety of injecting PMD patients with adult neural stem cells that can lead to healthy oligodendrocytes. They hope normal oligodendrocytes might be able to provide the needed myelin. Results of the clinical trial will be assessed in 2012.

“We are not trying to kill off the defective cells, but to restore the brain’s ability to produce a supply of normal myelin by providing healthy oligodendrocyte precursors,” said Rowitch, principal investigator on the trial and a pediatric specialist and chief of neonatology at UCSF Children’s Hospital. Rowitch also is a Howard Hughes Medical Institute Investigator in UCSF's Broad Center. “These cells have the capacity to identify areas of the brain lacking myelin, so if they can survive after transplantation they may be able to form myelin in the brain of PMD patients.” 

In the study, UCSF neurosurgeon and co-principal investigator in the trial Nalin Gupta transplanted “adult” neural stem cells directly into the brain of four patients.

Critical to monitoring the treatment’s progress, the trial calls for patients to receive MRI scans of their brains before the treatment and then every three months for a year to assure that the new cells do not cause widespread brain inflammation or other problems.

In addition, neurologist Jonathan Strober, also co-principal investigator, monitors the patients’ symptoms to identify any signs of clinical improvement or deterioration.

If the trial shows evidence of safety and of myelin production, it could point the way to a whole new approach to treating of PMD and other childhood brain disorders, said Rowitch says. 

“We still have much to learn about human stem cells therapies, but I hope we can look back on this time as the very beginning of a wave of treatments for intractable diseases,” said UCSF’s Kriegstein.

'Borrowing' a patient’s stem cells

In both the UC Irvine and UCSF clinical trials, a specific type of normal donor stem cell is introduced to patients. These precursors are expected to develop into healthy adult cells, restoring normal functions. Another type of treatment strategy involves removing millions of disease-carrying stem cells and genetically “curing” them — correcting the disease-causing genetic defect — and then transplanting the healthy cells back into the patient.

A UCLA team is developing such a gene therapy to cure sickle cell disease (SCD), the debilitating disorder that affects nearly 100,000 Americans, weakening many and often killing them before the age of 40. The genetic disease causes red blood cells to take on a sickle shape, clogging blood vessels and producing episodes of excruciating pain.

Most people with SCD have some type of brain blood vessel problem by the time they are 20, and about one in seven have severe strokes. Current medical treatments can provide short-term relief, but the disease leads to progressive deterioration in organ function. In even its milder forms, SCD prevents a normal blood supply, starving cells of oxygen and leading to episodes of severe bone and abdominal pain, breathing problems and progressive kidney damage.

Like many genetic disorders, SCD affects certain populations more than others. The single inherited defect in a single gene that causes the disease occurs more frequently in African Americans, with one in 500 people afflicted. About 5 percent of SCD patients in California are Hispanic Americans.

Donald Kohn, director of the Human Gene Medicine Program at UCLA and a scientist with UCLA’s Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, received a $9 million “Disease Team” grant from the California Institute for Regenerative Medicine (CIRM) to develop a stem cell treatment for the disease. For SCD patients, his team seeks to genetically correct their bone marrow adult hematopoietic stem cells — those cells that give rise to all types of blood cells — by adding a hemoglobin gene that blocks the sickling of the red blood cells. The healthy stem cells then will be transplanted back into the patients.

The strategy has the potential to permanently cure the illness with far less toxicity and risk than a bone marrow transplant from another person.

Kohn and his colleagues have shown in the laboratory that they can take cells from an SCD patient and genetically alter them to prevent sickling. After additional laboratory research, they will seek FDA approval to demonstrate that genetically corrected human bone marrow stem cells can be transplanted into SCD patients  and enable them to make normal red blood cells.

Kohn feels confident that his team can meet its target: human clinical trials within four years.

“This will be the sixth gene therapy clinical trial I have directed,” he said. “It’s a technically complex project, but I think the timeline is realistic. There is a desperate need for new approaches. It’s a very bad disease for many patients, and current therapies haven’t made patients much better.”

Astrocytes for ALS

A UC San Diego program to develop a treatment for amyotrophic lateral sclerosis, or Lou Gehrig’s Disease, received about $11 million in a CIRM-funded Disease Team grant. Larry Goldstein, professor of cellular and molecular medicine and director of the UC San Diego Stem Cell Program, heads the effort. Like UCLA’s Kohn, Goldstein plans to advance this research to a therapy that can move to clinical trials in just a few years.

People with ALS experience a rapidly progressive weakness, muscle atrophy and severe respiratory deficit among other grim effects, and most die after two to five years. The disease is caused by degeneration of neurons in the spinal cord and the brain.

No cures for ALS have been developed, but Goldstein and colleagues at UC San Diego and other institutions have found strong evidence that the disease not only damages neurons but also astrocytes, a type of cell known to provide critical support for neurons. The team’s studies in a rat version of ALS shows that injecting healthy versions of astrocytes into the spinal cord may rescue motor neurons and stop, or at least slow down, the devastating damage.

“It’s the death of motor neurons that leads to paralysis, but we think damaged astrocytes are a key part of the disease,” Goldstein says. “They normally provide nutrients to neurons and maintain an environment that is essential for neurons to survive and function properly.”

Goldstein's team wants to tweak human embryonic stem cells to become astrocyte precursors, and transplant these stem cells into spinal cords of ALS patients to at least partially restore normal function.

The team must convert stem cells to astrocyte precursors in a quantity large enough to be clinically useful. Millions are needed. Research with animals should help determine roughly how many stem cells would be needed for humans.

As director of UC San Diego’s stem cell program, Goldstein supports efforts to streamline these early days of research-into-treatments. His ALS project will use a single embryonic cell line for many different patients in order to retain control of safety and efficacy. One cellular product can be extensively tested and used on many patients, he says.

Goldstein champions the use of human stem cells to allow researchers to seek treatments by studying “diseases in a dish.”

“Animal models are important for understanding the basic principles of cell function, but animals are not human, and diseases impact different types of organisms differently,” he says.  “By testing drugs and other treatments directly on human cells we are very hopeful we can more quickly get to the payoff of therapies and cures.”