HD biomarkers in CSF

Huntington’s disease therapeutic and companion biomarker collaboration forged by KineMed, Isis Pharmaceuticals and CHDI Foundation

Lloyd Dunlap
EMERYVILLE, Calif.—KineMed Inc., Isis Pharmaceuticals Inc.and the CHDI Foundation Inc. are collaborating to utilize KineMed'stranslational biomarker platform with Isis' antisense therapeutic program forHuntington's disease (HD). This collaboration, which builds on an earlieralliance between CHDI and KineMed to develop companion biomarkers oftherapeutic response in HD, will provide Isis access to novel biomarkers foruse in the development of an antisense drug to treat HD.
 
"There is a critical need to identify appropriate biomarkersto determine target engagement and predict early clinical efficacy for futureHuntington's disease clinical trials," says Dr. Jonathan Bard, director ofmolecular pharmacology at the CHDI Foundation. "Combining Isis' knowledge ofantisense therapies with KineMed's expertise in developing uniquepharmacodynamic biomarkers creates a collaboration with great potential fordiscovering such tools for HD."
 
 
The companion biomarker partnership represents "personalizedmedicine in action," says Dr. Patrizia Fanara, vice president of neuroscienceat KineMed. "Our neurodegeneration-specific biomarkers, which provide dynamicmeasures of axonal transport deficits in degenerating brain cells, predicttherapeutic response in neurological and neuromuscular disorders. This is atranslational biomarker that could prove crucial to the advancement ofdisease-modifying treatments. With the Huntington's disease domain knowledgethat CHDI brings and the therapeutic approach that Isis is pioneering, thispartnership has the potential to develop biomarkers for specific therapeuticsfor HD and lead to personalized medicines for HD patients."
 
 
"There is a critical need to identify appropriate biomarkersto determine target engagement and predict early clinical efficacy for futureHuntington's disease clinical trials," says Dr. Jonathan Bard, director ofmolecular pharmacology at the CHDI Foundation. "Combining Isis' knowledge ofantisense therapies with KineMed's expertise in developing uniquepharmacodynamic biomarkers creates a collaboration with great potential fordiscovering such tools for HD."
 
 
Dr. Marc Hellerstein, chief scientific officer at KineMed,notes that until now, there has been no way to determine when HD actuallystarts, or why symptoms so often show up in individuals at about age 40.
 
"HD is a single-gene Mendelian disorder, but what are thecausal pathways?" he says. "Linking simple genetics to biology, which is notsimple, has been the challenge."
 
 
KineMed's neurodegeneration biomarker of axonal transportdeficit has been recently published in the Journalof Clinical Investigation and validated in patients with other neurologicaldisorders. The KineMed-led research identified a class of cerebrospinalfluid-based (CSF-based) kinetic biomarkers that reflect altered neuronaltransport of protein cargo, a common feature of neurodegeneration. The researchdata indicated that CSF kinetic biomarkers of axonal transport provide direct in-vivo metrics of neurodegenerationthat are translatable in humans.
 
 
According to Fanara, disease onset and progression are bothhighly variable.
"We can now monitor changes at the cellular level based onthe relationship between changes in the brain and CSF, and correlate thesechanges to clinical symptoms," she says.
 
 
KineMed CEO David Fineman says connecting biology togenetics will ultimately lead to the "missing link"—connecting biology totherapeutics.
 
 
Huntington's disease is an inherited neurodegenerativedisorder caused by a mutation in the huntingtin gene. The defect causes a DNAsequence called a CAG repeat to occur many more times than normal. Each childof a parent with a mutation in the huntingtin gene has a 50 percent chance ofinheriting the mutation. As a result of carrying the mutation, an individual'sbrain cells degenerate, leading to behavioral, cognitive and motor impairmentsthat, over the course of the disease, significantly reduce the individual'squality of life and ultimately cause death within 15 to 25 years of symptomonset. There are currently no therapeutics approved that slow the progressionof Huntington's disease.
 
 
"A pharmacodynamic biomarker could be an importantcontribution to our clinical development efforts, and we look forward toworking with KineMed and CHDI to evaluate KineMed's biomarker platform in ourHD program," says Dr. Frank Bennett, senior vice president of research at Isis.
 
 
Isis declined to provide further details on its therapeuticprogram.
 
 
 

Lloyd Dunlap

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