Harvard researchers have gleaned a clue as to how one of the most devastating neurodegenerative diseases eventually causes patients to lose control of the ability to walk, speak, and breathe, suggesting a possible new approach for developing drugs.
In amyotrophic lateral sclerosis, or ALS, nerve cells involved in movement within the brain and spinal cord die off. The new research shows that at least in a rare genetic form of the disease, the nerve cell die-off may stem from a toxic interaction with a different type of supporting cell, called microglia. Genetically tweaking mice to eliminate a particular protein that is the middleman in this harmful interaction resulted in a 6.7 percent increase in the life span of mice in the study.
Steve Perrin, the chief scientific officer of the ALS Therapy Development Institute in Cambridge, said that the research was an important and carefully executed first step — but only the very first step.
“The challenge you now have is the next phase of drug development, which is where we all spin our wheels and spend lots of money,” said Perrin, who was not involved in the research. “This is a great basic research finding, but if you want to make a drug that’s effective for a patient, this is the tip of the iceberg.”
To do their work, the researchers used genetic manipulation in mice to create microglia that carried the mutation associated with a small fraction of ALS cases and put those cells in a dish with healthy human motor neurons created from stem cells. They found that the mutated cells had a toxic effect on the motor neurons, as expected from previous experiments. They tried administering a chemical compound that blocked the protein they thought might be responsible and found that doing so reduced the damage to the neurons. When they genetically manipulated the mice to lack that particular protein, which is part of a family called prostanoid receptor, they found the animals’ life spans improved modestly.
“This publication now provides the irrefutable evidence that these receptors have a role to play and that eliminating their activity could be helpful in this context,” Eggan said. “So we’re optimistic about that moving forward.”
In a separate set of experiments in lab dishes, Eggan’s team found earlier this year that an approved epilepsy drug called retigabine could reduce the abnormally overactive behavior of neurons created from patients with ALS by reprogramming their skin cells. They hope to extend that work into a safety clinical trial by next year.
Perrin recently authored an essay describing a pervasive problem in the field of ALS, in which flaws in how animal studies are designed or conducted may produce misleading signals that the drugs will work in people. Clinical trials have moved forward at great expense to funders, companies, and patients, that could have been predicted to fail with more rigorous animal studies, Perrin argued. He said the current study is crucial because it does the hard work of validating the drug target.
But the questions yet to be answered are far from trivial: Any drug will have to be able to cross into the brain, and also avoid having negative effects on other cells in the body. For example, Perrin said, blocking the particular protein that is the focus of Eggan’s study has been shown in other scientific publications to trigger inflammatory processes in the lung, cause problems in the gut, and deplete cells critical for the immune system.