Stem cells produce anti-disease protein in brain experiment

A recent phase-one study at UW-Madison’s Waisman Center shows a potential new avenue for stem cell-based treatment of Parkinson’s and other neurodegenerative disorders. Their treatment could enable brain cells that generate dopamine, which helps the brain control the body’s movement, to recover from the damage caused by disease.

The study involved use of a naturally occurring protein in the brain called glial cell-derived neurotrophic factor, or GDNF, which has been found to help the brain keep generating dopamine. Experimental evidence in both animals and humans has shown that increasing the level of GDNF in the brain can help the dopamine neurons damaged by Parkinson’s disease.

Researchers used fetal stem cells coaxed into becoming progenitor cells—a midway form between their completely undifferentiated state and fully formed cells—implanted into the brains of lab rats. The progenitor cells were then able to form GDNF generator cells from within, continuing to function for up to three months.

“They’re not completely fated yet, but they will become a type of brain cell, potentially,” said Allison Ebert, a post-doctoral fellow involved in the study. “Since we’re transplanting them back into the brain, we use them for our delivery vehicles.”

By using progenitor cells, researchers were also able to lessen the risk of cell growth progressing beyond the intended purpose and resulting in tumors, a possible pitfall of stem-cell therapies. Ebert cautioned that this is only an early research step, with many other goals to be met before it can have further application in humans.

“We’re still quite a ways off, but some of the other studies using direct GDNF injection, rather than using the progenitor cells to secrete GDNF, those studies have been done in humans and there’s good positive data coming from those,” said Allison Ebert, a post-doctoral fellow involved in the study. “But in terms of our study we’re still a ways off because the behavioral impairments that are induced in these rats were not completely ameliorated.”

One problem remaining is how to fine-tune the progenitor cells to get the right level of GDNF generation; too little would be ineffective in treating the impaired movement, while too much could also result in abnormal movement. Ebert said this might involve precise formulation of the same lab-made virus that programs the cells to become GDNF generators, building it so it can reach the right level and then stop.

The study, published in the journal Gene Therapy, was authored by Soshana Behrstock, along with other scientists from UW-Madison and elsewhere. UW-Madison neuroscientist Clive Svendsen, a participant in the study, has also applied to the use the technique for patients suffering from amyotrophic lateral sclerosis, more commonly known as Lou Gehrig’s disease.

An obstacle to conventional pharmaceutical treatments has come from the blood-brain barrier, the membrane that keeps harmful chemicals from crossing over from the bloodstream to the brain. While evolution has honed the barrier to keep harmful toxins out, it also prevents conventional drugs and their beneficial effects from being able to help patients.

The new method is much less invasive than an earlier alternative tried by biotech firm Amgen, which had attempted to circumvent the barrier by directly injecting GDNF into the brain. The company halted follow-up trials, citing potential dangers; it involved daily infusions by a catheter pumping the factor directly into the brain.