Scientists at the Harvard Stem Cell Institute (HSCI) have developed a possible treatment for Amyotropic Lateral Sclerosis (ALS), also known as Lou Grehrig’s disease or Motor Neurone disease, derived from a recently approved anti-convulsive drug, Retigabine, which is recommended for Epilepsy.
ALS is one of the most common conditions affecting the motor neurones on the lateral side of the brain and spinal cord. It causes hardening (sclerosis) of these neurones with loss of signaling activity. Opinions on the exact cause of ALS remain divided. Some refer to over-excitation and hyperactivity of nerve fibers, while others blame free radical formation due to oxidative stress, defects in axonal transport, mitochondrial dysfunctions and accumulation of misfolded proteins due to faulty RNA processing, which cause more than 100 mutations in the genetic make-up of these neurones. The most commonly studied mutations include those of SOD-1 (Superoxide Dismutase 1), TDP-40 (Transactive Response Binding Protein) and FUS / TLS (Fused Sarcoma / Translated Liposarcoma).
Researchers at HSCI were led by principal faculty member Kevin Eggan, a professor in Harvard’s Department of Stem Cell and Regenerative Biology (who holds the credit for publishing the first paper on the utility of stem cells in studying ALS, in 2008), his colleague, Clifford Woolf, a Harvard Medical School professor in neurology and neurobiology and director of the neurology center at Children’s Hospital Boston, who also co-leads HSCI’s Nervous System Diseases Program, Evangelos Kiskinis, a postdoctoral fellow, and Brian Wainger, a neurologist at the Harvard Medical School.
Funding for this study was provided by Target ALS, Project A.L.S., P2ALS, the National Institute of Neurological Disorders and Stroke, the Howard Hughes Medical Institute, the National Institutes of Health Director’s Pioneer Award, Harvard NeuroDiscovery Center, the ALS Association, the American Brain Foundation, ALS Therapy Alliance, the Angel Fund, Pierre L. de Bourgknecht ALS Research Foundation, Al-Athel ALS Research Foundation, ALS Family Charitable Foundation, and the New York Stem Cell Foundation.
According to a report released by Harvard University, dated April 3, 2014, the study included isolation of stem cells from the skin of female ALS patients. Neurones were generated from these cells, which represented ALS on an in-vitro platform. RNA sequencing was done to trace the changed expressions of genes. It was noted that misfolded proteins lead to genetic mutations which result in hyperexcitability of neurones. This was hypothesized to put neurons in a vulnurable position, wherein they died. On treating these cells with Retigabine, scientists received a positive response, which was a first-in-human cell study.
According to Prof. Eggan, “The big problem in ALS is that there are more than 100 mutations in dozens of genes that all cause the disease, but almost all of the therapeutics that have gone forward in the clinic have done so for just one of those mutations, SOD1, which almost everyone studies in mice. And so, the key question that we really wanted to address was: Are clinical efforts failing because the mouse is taking us on a wild goose chase, or is it simply that people haven’t had the opportunity to pretest whether their ideas are true across lots of forms of ALS?”
However, on studying the genetic sequence changes and the molecular basis of ALS in-vitro, and comparing them to mouse models, Eggan said, “We found that the mutation makes changes in the motor neurons, which aren’t so different from the changes that you see in the mice. I think our paper says that while there are definitely some human-specific biology, the mice weren’t totally misleading.”
Commenting further on their findings, Woolf said, “It looked like there’s a deficit in potassium channels in the ALS motor neurons, and that led us to then test whether drugs that open the potassium channels may reduce this hyperexcitability. And indeed that’s exactly what we found. We found that Retigabine, normalized this activity. So now we can formally go from the dish to the patient and actually explore whether the drug might have any beneficial effect.”
Now that a particular target for therapeutic intervention has been agreed upon, Massachusetts General Hospital neurologist, Dr. Merics Cudkowics, along with Brian Wainger, will be working on human trials to check for the safety and efficacy of the drug. The treatment is expected to take a long time to be approved as an established treatment option, considering the complexity of the nervous system. But nonetheless, it can be taken as a progressive step towards the treatment of such complex neurodegenerative disorders.
Dr. Woolf stated, “I think it’s the beginning of a complete change in the way we do medicine for serious diseases like this. In a traditional clinical trial, you give the patient the placebo or an active ingredient to see the effects they have, and it’s over. Here we can take the same stem cell lines and have an infinite capacity to do clinical trials in a dish.”