NEW YORK—Project A.L.S. has forged an agreement with Eli Lilly and Co. aimed at helping to accelerate the development of potential therapies for the neurodegenerative disease amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease. As part of the agreement, Project A.L.S. will study molecules developed and studied preclinically by Lilly scientists for the treatment of cancer to assess their potential in the treatment of ALS.
Research sponsored by Project A.L.S. and conducted by Dr. Tom Maniatis and Dr. Thomas Jessell, both professors at Columbia University, uncovered novel data that identified a critical role in ALS disease progression for several inflammatory signaling pathways that are also known to be associated with cancer.
“Chronic inflammation has long been implicated in ALS disease progression, but recent advances in areas like genomics have now made it possible to identify specific inflammatory targets for ALS drug development,” said Dr. Maniatis.
Lilly has a robust oncology pipeline, including several preclinical molecules targeting the signaling pathways proposed to be involved in cancer and inflammation. Project A.L.S. will study select Lilly molecules in preclinical ALS models to determine if these molecules show any activity between ALS and inflammation.
“The evidence demonstrating a potential role for these cancer signaling pathways in the progression of ALS is compelling,” said Dr. Greg Plowman, vice president of oncology research at Lilly. “Lilly will provide well-characterized and selective molecules that we hope will help accelerate the development of medicines for ALS.”
The Project A.L.S. research advisory board has identified and prioritized five strategies for 2013-2015 to progress toward the goals of finding the first effective treatments and a cure for ALS. The 5 IN 3 program—five projects in three years—is described by the non-profit organization as “a diverse, integrated portfolio ranging from basic research to preclinical studies.”
One of those projects, focused on motor neuron resistance, is directed by Dr. Elizabeth Engle of Boston Children’s Hospital and Harvard Medical School. As Project A.L.S. notes, ALS destroys almost all types of motor neurons, but some—such as those controlling eye movements—survive the disease. Engle’s team will pursue clues as to why certain sub-populations of motor neurons are resistant in ALS and devise approaches for making vulnerable motor neurons resistant.
Another of the projects targets inflammation and is directed by Jessell and Maniatis. Three years ago, several leading ALS research labs concluded that in ALS, brain cells called astrocytes become toxic to motor neurons. Recently, the laboratories of Jessell and Maniatis took a major step in understanding this toxicity when they identified several genes in motor neurons that are significantly upregulated in the presence of ALS astrocytes. These upregulated genes participate in two well-described pathways of inflammation. This team is now working to target the implicated inflammatory pathways in ALS with combinations of FDA-approved drugs for other diseases in which inflammation plays a major role. Preclinical trials are currently underway.
A third project, directed by Dr. Robert H. Brown Jr. of the University of Massachusetts, looks at gene silencing, and Project A.L.S. notes of this effort that scientists have identified 24 genes that contribute to various forms of ALS. One strategy for slowing or stopping ALS is to use emerging delivery methods—including small molecules, siRNAs and viruses—to silence these genes and, thus, their effects. The first patient trials will focus on silencing SOD1 and C9orf, genes implicated in both familial and sporadic ALS.
Dr. Chris Henderson and Dr. Hynek Wichterle of Columbia University are heading up the fourth of the five projects, which is associated with the Jenifer Estess Laboratory for Stem Cell Research, a stem cell lab established in 2006 as the world’s first privately funded laboratory to work exclusively with stem cells and ALS. Since then, the laboratory has built a library of ALS patient-derived motor neurons that allows researchers all over the world to study the cells affected in the disease.
Finally, there is the Blue Sky Initiative , a project headed by Dr. Nancy Bonini of the University of Pennsylvania and Dr. Arthur Horwich of Yale University, who have launched a targeted outreach to young and experienced scientists who will be chosen for their ability to bring fresh perspectives and ideas for therapies to ALS and related neurodegenerative disease research. Each Blue Sky researcher receives three-year support for one set of proof-of-principle experiments.