Bad luck stalked the early years of gene therapy. The pioneering research revealed it is difficult to manipulate a patient’s genes both efficiently and safely. Today, after more than two decades of tireless labor in the lab, nearly 2,000 gene therapy trials have been conducted or are approved, with many of the most promising using stem cells to carry the genetic tricks.
CIRM is providing $110 million in funds for nine projects that have made it into the clinic—or hope to get there soon—by marrying the power of gene manipulation and stem cells. We have several other projects combing the two therapy tools in earlier stages of development.
The first gene therapy trial in the U.S. in 1990 sought to cure Severe Combined Immune Deficiency (SCID), or ‘bubble-baby disease,” and produced modest success. But it did not last. The gene-modified cells did not stick around. Much tinkering ensued to create better ways of getting the desired therapeutic gene into cells, but one of those new tools resulted in the death of a patient in a clinical trial in 1999. That death of Jesse Gelsinger led the Food and Drug Administration to suspend several ongoing clinical trials. Then the 2003 death of a SCID patient from leukemia, believed to have been caused by another gene delivery approach, further dampened the field.
But researchers who see great potential for treating unmet medical needs are not easily dissuaded. The pioneers of gene therapy studied why the deaths occurred and found gene delivery tools that would not go down those same unsafe paths. They discovered ways to get the genes expressed by cells efficiently and longterm. CIRM grantee at the University of California, Los Angeles (UCLA), Don Kohn was helping lead the charge in the early days; despite setbacks he stuck with it, and last year announced that 18 kids had been cured of SCID using stem cells modified to produce the protein missing in the disease. He has just launched a clinical trial hoping to vanquish sickle cell anemia in the same way.
CIRM clinical projects combining stem cells and gene manipulation fall into three categories:
- Genetic fix when someone is born with a mutated copy of a gene.
- Gene modification to alter stem cells to give them a desired trait.
- Gene insertion as drug delivery to give cells a boost of a naturally occurring protein.
Both of the CIRM genetic fix projects seek to rectify errors in the gene for hemoglobin, the protein that our red blood cells use to carry oxygen. Kohn explains his work to provide a working copy of a hemoglobin gene in sickle cell patient’s blood-forming stem cells in our “Stem Cells in Your Face” video series.
Sangamo’s clinical trial won’t be correcting the defective hemoglobin gene in Beta Thalassemia patients directly, but instead will edit the patient’s genes to turn on the gene for fetal hemoglobin that is not normally active as an adult. The company’s team has shown that this gene can produce enough of the protein to end the patients’ need for constant blood transfusions, which up until now has been the only way for them to get healthy red blood cells.
Genetically modifying stem cells to give them desired traits comes in many forms. The two HIV/AIDS projects both seek to alter patients’ blood-forming stem cells so that they produce T cells that are immune to infection by the virus. City of Hope scientists, working with Sangamo, devised a way to alter a protein on the surface of T cells, called a receptor that the virus uses like a door to gain entry into the cells. It is like taking away the key so the virus can’t get in. The Calimmune team doubled down on door security. They are altering two different receptors the virus uses for entry.
Both of the cancer projects seek to alter blood-forming stem cells so that they produce immune system cells that are better targeted to killing a patient’s specific tumor.
Gene insertion to act as a “drug” delivery system also has diverse applications. The Huntington’s disease project uses a type of stem cell found in bone marrow called a mesenchymal stem cell (MSC) to deliver a nerve growth factor that has been shown to be protective of nerves facing the type of damage seen in Huntington’s.
The ALS project starts with cells called neural progenitors, “teenaged” cells that are only part way along the path of maturity between a nerve stem cell and the final adult brain cells. Once transplanted the cells should have a two-pronged benefit. They mature specifically into astrocytes, the initial brain cell to go bad in ALS, and the added gene will produce a growth factor that has been shown to be protective of the damage seen in ALS—a different growth factor than the one used in the Huntington’s research.
In limb ischemia, poor blood circulation and severe pain results from clogged blood vessels, so therapies that stimulate growth of new vessels make sense. A growth factor called VEGF has long been known to do this, but when doctors tried injecting it into aching legs it didn’t stick around long enough to do any good. MSCs are also known to stimulate blood vessel growth and have shown some benefit when transplanted into patients with limb ischemia. If that benefit could be ratcheted up patients could gain significant pain relief. The UC Davis team hopes to transplant MSCs that have an extra copy of the VEGF gene so they stimulate vessel growth through two paths.
The marriage of gene therapy and stem cell therapy seems likely to produce a number of live-happily-ever-after therapies.