Wednesday, May 19, 2010

Drug Development for Neurodegenerative Diseases Conference Part 1

Prize4Life is pleased to bring you exclusive coverage as the conference blogger for Drug Development for Neurodegenerative Diseases, a conference organized by marcus evans. With over 40 representatives from industry and academia, the conference is focused on new therapeutic developments, biomarkers, target identification, and issues in clinical trial design for neurodegenerative disease. Without further adieu we bring you the round-up from day one….

The first set of sessions focused on current updates in therapy development for neurodegenerative treatment.

First up was a joint presentation entitled: Protein Kinase C: A Basis for Biomarkers and Therapeutics for Alzheimer’s Disease co-presented by Drs. C. Anthony Altar and Daniel Alkon of the Blanchette Rockefeller Neuroscience Institute.

This first set of presentations focused on a signaling pathway that may serve as a new target for Alzheimer’s Disease (AD) and eventually other neurodegenerative conditions. A key deficit common across neurodegenerative disease is the loss of synapses, the contact and communication point between cells of the nervous system. Activation of the molecule Protein Kinase C-epsilon appears to mitigate and potentially even reverse synapse loss.

As the presenters explained, dramatic pathologic changes like plaques and tangles are late events in Alzheimer’s, “tombstones rather than precursors”. Early events, like the loss of synapses (a process that occurs well before formation of the famous plaques and tangles we usually hear about), correlate well with a given individual’s degree of dementia, but plaques and tangles don’t. Given that memory loss is the hallmark of AD, the presenters were interested in gaining a better understanding of the molecular changes that store memory: changes in the synapse.

Dr. Tony Altar, the former director of The Biomarkers Consortium for the Foundation for the National Institutes of Health, and the current Director of the Alzheimer’s Diagnostic Laboratory of the Blanchette Rockefeller Neurosciences Institute, spoke first.

He presented recent data indicating that defects in PKC-epsilon signaling can be sensitively detected in cultured skin cells called fibroblasts. Moreover, he showed that the PKC-epsilon pathway defects seen in cultured fibroblasts from AD patients were similar to those found in postmortem AD brain tissue. The implication is that these easily accessible fibroblast cells can be used to potentially diagnose and screen treatments for Alzheimer’s Disease (and potentially other neurodegenerative diseases). Using fibroblasts from both patients with presumed AD and control patients without the disease, Dr. Altar showed that his lab could use fibroblasts to distinguish these two populations with a high degree of sensitivity and specificity.

In future studies his group hopes to further refine the system so as to provide early diagnosis of AD and discriminate AD from other forms of dementia, thereby allowing better stratification of patients for therapeutic trials and treatments.

In a companion presentation, Dr. Daniel Alkon, Scientific Director of the Blanchette Rockefeller Neurosciences Institute, delved into how his group was using knowledge of the PKC-epsilon pathway to develop potentially novel AD treatments.

PKC-epsilon is a form of Protein Kinase C found almost exclusively in the brain. Dr. Alkon’s group has identified a class of compounds that can activate PKC-epsilon without any obvious toxicity and with good blood brain barrier penetrance, ideal qualities for a drug to treat diseases of the brain!

Their lead compound, bryostatin, is able to prevent and reverse the damage seen in the brains of a variety of different models of AD transgenic mice. Intriguingly, bryostatin has also been shown to induce synapse formation in an animal model of Fragile X, a disease in which animals are born missing many synapses, suggesting that this drug may be efficacious even when administered late in AD disease progression after significant synaptic loss has already occurred.

Dr. Alkon is now preparing for an FDA-approved phase II trial of bryostatin (which had previously been shown to be safe in a large cancer trial). Our reporter probed as to whether these researchers would consider testing bryostatin in motor neurons and/or ALS mouse models and was pleased to hear a yes! This identification of the critical role of certain members of the Protein Kinase C family in synapse formation and maintenance holds potential implications for all diseases and disorders in which neuronal cell communication is disrupted. A promising avenue of discovery Prize4Life will continue to track closely.

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