This article has been updated from a previous version to correct several errors. First, the company is using a proprietary, not an established, cell-protection screen in the SOD1 study. The original article also referred to the fer1 gene instead of the dysferlin gene in describing the ALS study.
Cambria Biosciences, a biopharmaceutical company based in Woburn, Mass., has received $5 million in five federal and non-profit awards to harness cell-based assay methods to discover preclinical candidate compounds for the neurodegenerative disorders amyotrophic lateral sclerosis, limb girdle muscular dystrophy, and Parkinson’s disease, the company announced this week.
Together, the awards will enable the company to optimize its compounds chemically for potency, efficacy, and desirable pharmacological properties, and test them in rat and nematode models of ALS with the eventual goal of filing with the US Food and Drug Administration.
“Basically, the funding should take us all the way up to the point of submitting an IND application to the FDA,” Donald Kirsch, senior vice president for drug discovery at Cambria, told CBA News this week.
The National Institute of Neurological Disorders and Stroke has awarded Cambria a one-year Phase 1 Small Business Innovation Research grant to help it identify small molecules that protect motor neurons against the cellular damage caused by the mutant copper-zinc superoxide dismutase 1, or SOD1, protein.
“Perhaps the best characterized example of a neurodegenerative protein-misfolding disorder is familial ALS, [which is] caused by a mutation in the gene encoding SOD1,” according to Kirsch.
As part of the first phase of the grant, which began on Sept. 1, 2007, the company will aim to identify compounds that block or reverse the effect of protein aggregates by using a proprietary high-throughput cell-protection screen based on the toxic effects of G93A mutant SOD1 expression in PC12 cells, Kirsch said.
Cambria will also try to identify compounds that block or reverse the formation of protein aggregates by running a high-content screen using PC12 cells that express G85R SOD1-YFP and in which protein aggregation can be directly observed and quantified.
Kirsch said that Phase 2 will evaluate compounds for therapeutic potential.
“This research really fills an important niche that is central to the mission of the NINDS, which is to find ways to treat or prevent neurological disorders such as ALS,” said Lorenzo Refolo, program director for neurodegeneration at NINDS.
Meanwhile, the ALS Association announced on Nov. 6 that it has awarded Cambria a multi-year, $3.5 million contract to develop new drug compounds to treat ALS.
By partnering with biotechs such as Cambria, ALSA hopes to find effective treatments for ALS, Lucie Bruijn, science director and vice president at ALSA, told CBA News this week. She said the award is part of the group’s Translational Research Advancing Therapy for ALS, or TREAT ALS, program, which aims to accelerate the clinical testing of promising ALS therapies.
According to ALSA, the funding builds on previous efforts with Cambria to identify novel neuroprotective compounds. Cambria and Northwestern University investigators presented initial findings from the ongoing project at the Society for Neuroscience international meeting in San Diego on Nov. 6.
The company won an award from the ALS Therapy Alliance to help it test the efficacy of certain of its oral small molecule compounds in preclinical animal models of ALS.
“The funding should take us all the way up to the point of submitting an IND application to the FDA.”
Cambria’s Kirsch said the company is collaborating on all ALS research with the labs of Rick Morimoto and Richard Silverman at Northwestern University, and with Boston University investigator Robert Ferrante.
Finally, Cambria received funds from the Jain Foundation for a year-long project to study LGMD2A and Miyoshi myopathy, Kirsch said. LGMD is a genetic disease caused by a mutation in the dysferlin gene. The dysferlin protein is believed to be involved in membrane repair, Kirsch explained.
Patients with dysferlin mutations are unable to repair their muscle membranes, resulting in muscular dystrophy.
Kirsch said that Cambria’s project, led by Cambria’s Mohan Viswanathan, uses C. elegans as a platform for high-throughput compound screening to identify potential small molecule therapies for LGMD2B and MM. C. elegans FER-1 is homologous to human dysferlin, according to Kirsch.
C. elegans fer-1 mutants show defects in spermatocyte maturation, which profoundly affect sperm motility and egg fertilization, Kirsch explained. This cellular process is highly homologous to the membrane repair defect found in patients with fer1 mutations.
The major focus of Cambria’s and Viswanathan’s research will be to identify chemical suppressors of the C. elegans fer-1 fertility defect because they believe compounds that restore fertility have promise as potential therapies for LGMD2A and MM, said Kirsch.
“In this case we are really not asking a mechanistic question at all. We are saying, ‘We know what is wrong, we just want compounds that fix it,’” said Kirsch. He said that later on, the company will determine their mechanism of action, which may, in addition to identifying leads for clinical drugs, potentially produce mechanistic information about new drug targets, he said.
The NINDS has awarded Cambria a second Phase 1 SBIR grant to identify compounds that activate the protein DJ-1 as potential therapies for Parkinson’s disease. Kirsch said that Parkinson’s disease, much like ALS, comes in both sporadic and familial forms.
“As with ALS, some of the best evidence of the etiology of Parkinson’s disease comes from the genetic forms,” he said.
One of the genetic forms of Parkinson’s is caused by mutations in DJ-1, which seems to have a protective effect on cells, said Kirsch. He said that DJ-1 appears to protect the cells from oxidative stress, which is believed to be a major reason why cells die in individuals with Parkinson’s.
“Presumably, if having too little of the protein causes the disease, producing extra amounts of DJ-1 might protect against the disease or halt or slow progression of the disease,” Kirsch said.
The objective of this grant is to use a high-throughput screen and then a secondary assay screens to identify inducers of DJ-1 expression, screen a proprietary library of approximately 50,000 compounds, and select DJ-1-inducing compounds for preclinical evaluation in phase 2, said Kirsch.
Bethany Westlund at Cambria is collaborating on this project with Jin Xu at Tufts-St. Elizabeth Medical Center, Kirsch said. “Cambria will be producing the lead compounds and Xu, as an expert on DJ-1, will be taking those compounds and characterizing their activity, both to understand how they work and to validate them as bona fide active compounds.”