Studies converge on ALS

Veronica Meade-Kelly, April 4th, 2014
  • Motor neurons deteriorate during the course of ALS. Researchers
    from the Broad, Harvard Stem Cell Institute, and Boston Children’s
    Hospital used stem cell, RNA-sequencing, and genome-editing
    technologies to investigate why these particular neurons are
    selectively affected.
    This graphic of a motor neuron was cropped from an original image
    by John Wildgoose, Wellcome Images under the Creative Commons
    BY-NC-ND 4.0 license

What: Researchers from the Broad Institute, the Harvard Stem Cell Institute (HSCI), and Boston Children’s Hospital (BCH) used an eclectic combination of cutting-edge technologies to determine what’s going wrong at the molecular level in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. Their research, published online this week in two separate Cell journals, sheds light on the mechanisms that lead to the disease and highlights potential targets for new treatments.

ALS is characterized by the degeneration of motor neurons, leading to a progressive and fatal loss of muscle control. While the disease has previously been linked to various mutations in over two dozen genes, it hasn’t been clear how these mutations lead to cellular degeneration, or why motor neurons are selectively affected.

One of the current studies, led by Broad associate member Kevin Eggan and first authors Evangelos Kiskinis and Jackson Sandoe, used a combination of stem cell, RNA-sequencing, and genome-editing technologies to investigate this medical mystery. By creating a stem cell line of motor neurons derived from ALS patients with known genetic mutations, they were then able to observe how those cells functioned – both during the course of degeneration and when the mutations were corrected. That comparison allowed them to identify mechanisms and genes that could be targets for potential therapies.

Eggan’s team also worked on the second paper, along with co-senior author Clifford Woolff and co-first author Brian Wainger of BCH and HSCI. That study used stem cell lines to confirm that motor neurons from ALS patients are “hyperexcitable” – firing too easily or too often – making the neurons vulnerable and prone to cell death. By introducing a drug that blocked the hyperactivity, they were able to counteract motor neuron degeneration in the patient-derived cells.

Who: Researchers from the Broad’s Stanley Center for Psychiatric Research, the Harvard Stem Cell Institute, and Boston Children’s Hospital conducted the study in partnership with scientists from six other institutions. In addition to Eggan, Kiskinis, and Sandoe, other Broad researchers involved include Steve McCarroll, Luis Williams, Rob Moccia, Steve Han, Ole Wiskow, Theodore Peng, Shravani Mikkilineni, Florian Merkle, Brandi Davis-Dusenbery, Michael Ziller, Justin Ichida, Nick Atwater, James Nemesh, and Bob Handsaker.

Why: The Broad’s Stanley Center for Psychiatric Research conducts research, on its own and in collaboration with partnering institutions, aimed at rooting out the genetic and molecular causes of neurological diseases, including ALS. The center’s ultimate goal is to translate those findings into promising new therapeutics.

“Emerging technologies are now enabling us to probe the biology of disease and test candidate drugs in a context that effectively mimics the cellular systems of patients,” explained Eggan, who is also a principal investigator at HSCI and a Howard Hughes Medical Institute Early Career Scientist. “By combining these approaches, we were able to identify a series of pathological mechanisms and possible drug targets in ALS – findings that we hope in time will benefit patients.”

Where to find it: Kiskinis et al. appears in Cell Stem Cell. Wainger et al. can be found in Cell Reports.

For more: Visit the Stanley Center for Psychiatric Research on the web to learn about more Broad research on neurological disease.