The 2013 European Latin American Neurology Symposium (ELANS) will take place April 25th-28th in San Diego, CA.  ELANS is an international meeting for healthcare professionals that focus on the investigation of neurodegenerative and cerebral vascular diseases as well as on the daily clinical practice with affected patients and their surroundings. The aim of it, is to discuss advances in the investigation within that spectrum of diseases, perspectives on outcome, be it short or long term, as well as clinical and ethical questions that arise during the daily work with patients, their families, caregivers and healthcare professionals. Click here to review program.

The 2013 ELANS meeting was organized by EVER Neuro Pharma in cooperation with Neuropore Therapies.

For more information please visit the meeting website at elan-symposium.org.

Neuropore scientists presented autophagy program data at the 2013 AD/PD meeting March 4^th -10^th, in Florence, Italy.

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*Published abstract #A-459-0013-01569, 2013 AD/PD meeting in Florence, Italy.

Development of a novel series of PI3K modulators designed to promote autophagy and the cellular clearance of neurotoxic peptides

Wolf Wrasidlo^1,2, Igor Tsigelny², Diana L. Price¹, Douglas W. Bonhaus¹, Amy D. Paulino¹, Herbert Moessler^1,3, Edward Rockenstein², Eliezer Masliah²

¹Neuropore Therapies, Inc., San Diego, CA 92121.
²University of California, San Diego, Department of Neuroscience and the Alzheimer’s Disease Research Center (ADRC), La Jolla, CA 92093.
³EVER Neuropharma, Unterach, AUSTRIA

Background:  Dysregulation of autophagy and consequent cellular accumulation of aberrant toxic protein aggregates may be the common underlying basis of many neurodegenerative disorders. Autophagy can be modulated via the AKT-mTOR pathway and pharmacological inhibitors of this pathway, such as rapamycin acting at mTOR, activate autophagy and to have beneficial effects in animal models of neurodegenerative disorders.

Objectives: Since PI3K regulates the AKT-mTOR pathway we tested whether a novel series of PI3K modulators could affect the AKT-mTOR pathway, increase autophagy and promote the clearance of aberrant neurotoxic proteins.

Methods: Structure-based design was used to generate a series of structurally novel ligands aimed to interact with a selected region of the catalytic domain of PI3K. In vitro and in vivo studies were then conducted to characterize the effects of these molecules on the AKT-mTOR pathway, cellular markers of autophagy and the clearance of amyloid-beta and alpha-synuclein. 

Results: NPT-520-34 inhibited the PI3K-AKT-mTor pathway, promoted autophagy, and reduced Abeta1-42 oligomers or alpha-synuclein accumulation in vitro. NPT-520-34 has favorable ADME properties, good oral bioavailability (29%), and no identified safety issues. In vivo studies confirmed biological activity, promotion of autophagy, and clearance of neurotoxic peptide oligomers.

Conclusions: A novel PI3K modulator, NPT-520-34, reduced alpha-synuclein accumulation and toxicity both in vitro and in vivo by increasing autophagy mediated clearance of oligomers. Studies are underway to assess the utility of NPT-520-34 as a potential therapeutic for the treatment of a wide range of neurological disorders including Alzheimer’s disease, Parkinson’s disease, multiple systems atrophy and dementia with Lewy bodies.

UCSD researchers presented the results of in vivo evaluations of Neuropore synuclein-targeting compounds at 2012 SFN meeting October 13th-17th, in New Orleans, Louisiana.

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*Published, 2012 Society for Neuroscience, Abstract 53.25.

Novel heteroaromatic organic compound normalized calcium abnormalities in α-synuclein transgenic Parkinson’s Disease-like mice model

Reznichenko L.¹, Cheng Q.¹, Mante M.¹, Saisan P.A.¹, Rockenstein E.M.¹, Overk C.¹, Tsigelny I.F.^1,3, Wrasidlo W.^4,5, Price D.L.⁵, Dale A.M.^1,2, Devor A.^1,2,6, Masliah E.¹

¹Neurosciences, ²San Diego Supercomputer Ctr., ³Moores Cancer Ctr., ⁴Radiology, UCSD, San Diego, CA;⁵Neuropore Therapies Inc., San Diego, CA; ⁶Massachusetts Gen. Hospital, Athinoula A. Martinos Ctr. for Biomed. Imaging, Harvard Univ., Charlestown, MA

Abnormal accumulation of α-synuclein is central to the pathogenesis of many disorders with Parkinsonism and dementia. Recently, using in vivo two-photon laser scanning microscopy, we demonstrated that neurons in the somatosensory cortex of transgenic mice expressing wild-type human α-synuclein exhibit pathological calcium activity. The most evident pathology was observed in response to repetitive stimulation – when subsequent stimuli were presented before the calcium signal returned to baseline – and was characterized by augmented, long-lasting calcium transients with considerable deviation from the exponential decay. These alterations were detected in the absence of a significant increase in neuronal spiking response, consistent with the hypothesis that α-synuclein promotes calcium alterations via interference with intrinsic cellular calcium buffering mechanisms. In the present study, we used this augmented calcium response as an in vivo functional biomarker of pathology and explored the therapeutic potential of a novel α-synuclein stabilizing agent: heteroaromatic organic compound-01 (HAOC-01). HAOC-01 was designed to bind the hydrophobic NAC domain of α-synuclein and to alter α-synuclein monomer structure, preventing binding of the α-synuclein monomer to cellular membranes and other α-synuclein molecules. The drug was administered acutely during an imaging session by intracortical microinjection. We established the pre-treatment baseline in each α-synuclein transgenic mouse by imaging calcium activity in individual cortical neurons in response to a train of 3 sensory stimuli delivered at 3 Hz (electrical whisker stimulation, 1 mA). Calcium measurements were repeated in the same neurons every ~15 min, while HAOC-01 (10 µM) was microinjected into the cortical tissue within the imaged area for 100 ms, 2 s prior to each sensory stimulus delivery. In agreement with our previous data, pre-treated neuronal calcium transients were characterized by an abnormal increase in the amplitude in response to each consecutive stimulus in the train. Administration of HAOC-01 reversed the pathological augmentation in the calcium response ~1 h after the beginning of microinjections. The effect was specific to HAOC-01 because vehicle-treated transgenic mice exhibited no improvement. These results suggest that synuclein-stabilizing agents may normalize α-synuclein-related changes in calcium homeostasis.

Neuropore scientists presented Abeta-protein program data at the 2012 Alzheimer’s Association International Conference (AAIC) meeting July 14^th -19^th, in Vancouver, British Columbia.

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*Published abstract #29624, 2012 AAIC meeting in Vancouver, B.C. (July 13-19^th)

NEUROPROTECTIVE EFFECTS OF A NOVEL ABETA-PROTEIN STABILIZER IN AN APP TRANSGENIC MOUSE MODEL OF ALZHEIMER’S DISEASE

Diana L. Price^*1, Wolf Wrasidlo^1,2, Igor Tsigelny², Douglas Bonhaus¹, Amy D. Paulino¹, Michael Mante², Chandra Inglis², Anthony Adame², Herbert Moessler^1,3, Edward Rockenstein², Eliezer Masliah²

¹Neuropore Therapies, Inc.,  San Diego, CA  92121.
²University of California, San Diego, Department of Neuroscience and the Alzheimer’s Disease Research Center (ADRC), La Jolla, CA 92093.
³EVER Neuropharma, Unterach, AUSTRIA

Background:

Alzheimer’s disease (AD) is a common, debilitating neurodegenerative disorder afflicting the aging population. Synaptic accumulation of Abeta (Ab)-protein oligomers and tau might be responsible for the neurological damage in AD. Thus, special interest has emerged in developing treatments that reduce the formation or facilitate the clearance of these oligomers. Utilizing molecular modeling and structure based design techniques we generated a series of novel organic heterocyclic compounds that are capable of recognizing the aggregated Ab-protein molecule and promoting clearance. Using cell-free and cell-based assays, a compound denominated NPT-400 with activity in the high nanomolar range was identified for pharmacokinetic (PK) and preliminary efficacy studies in APP transgenic (tg) mice.

Methods:

The mThy1-hAPP751 transgenic mouse was utilized for efficacy studies. This mouse combines the Swedish (K670M/N671L) and London (V717I) APP mutations, and these animals develop AD-like neuropathology and behavioral deficits starting at 3-4 months of age.   Female non-tg and tg mice (~5 mo of age) received a single injection of vehicle or NPT-400-3 (IP, 10 mg/kg) three times per week for 6.5 weeks.  Behavioral assessments were conducted during week 4 of treatment including locomotor activity and water maze.  At the completion of treatment, brains were hemisected and tissue sections were processed for immunolabeling and confocal analysis, and homogenates were analyzed for levels of Ab-protein by ELISA and immunoblot. For PK studies, wildtype C57Bl6 mice received IV or PO NPT-400-3 compound at 10 mg/kg and blood and plasma levels were analyzed at 0-24 hrs.

Results:

Treatment with NPT-400-3 resulted in a statistically significant normalization of locomotor activity accompanied by amelioration of the synaptic and dendritic pathology in the neocortex and hippocampus. By immunoblot and ELISA the levels of monomeric and oligomeric Ab-protein were statistically significantly reduced in the brains of the APP tg mice. PK studies showed that NPT400-3 is stable in plasma, is orally bioavailable and penetrates the brain with a B/P ratio of 0.8 .

Conclusions:

NPT-400-3, is an orally bioavailable, brain penetrating Ab-protein stabilizing organic compound that reduces the accumulation of Ab-protein oligomers and ameliorates behavioral deficits and neuropathology in APP tg mice without overt adverse effects.

Neuropore and UCSD researchers presented the results of synuclein program experiments at the 2011 SFN meeting November 12^th-16^th, in Washington, D.C. 

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*Published, 2011 Society for Neuroscience,   Abstract 357.25.

Novel structure based designed compound reduces accumulation of toxic alpha-synuclein and improves deficits in a transgenic murine model of PD/DLB

D. L. PRICE¹, A. D. PAULINO¹, T. GONZALEZ-RUELAS², K. UBHI², E. ROCKENSTEIN², I. TSIGELNY³, W. WRASIDLO⁴, H. MOESSLER¹, E. MASLIAH²

¹Neuropore Therapies, Inc., San Diego, CA
²Neurosciences, ³Chem. & Biochem., ⁴Moores Cancer Ctr., UC San Diego, La Jolla, CA

Abnormal accumulation of a neuronal protein alpha-synuclein has been hypothesized to underlie neuronal cell death and dysfunctional connections Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB).  We have developed and utilized structure-activity relation (SAR) simulations (Tsigelny et al., 2008) that have allowed us to design and synthesize a novel series of new compounds, including the bicyclic peptidomimetic compound IIPP-1, that hold the promise for the “disease modifying” treatment of PD by selectively blocking the formation/accumulation of toxic forms of alpha-synuclein.  Here we report the results of in vitro characterization, as well as preliminary efficacy studies of IIPP-1 in a transgenic mouse model of PD/DLB.

Evaluation of IIPP-1 in vitro activity demonstrated that this compound potently inhibits the formation of alpha-synuclein oligomers in cell free and cell based assays, increases calcium and calcein recovery, and decreases markers of cell toxicity.

Based on these results, small-scale efficacy studies were conducted to evaluate the therapeutic potential of IIPP-1 in the Thy-1-ASYN transgenic animal model of PD (Rockenstein et al., 2002).  This transgenic mouse develops PD-like motor and non-motor deficits as well as neuropathological indices (including alpha-synuclein aggregates and decreases in synaptic markers) starting as early as 3 months of age.

In the present study, non-tg and tg THY1-ASYN male mice treated daily with 0, 1 or 5 mg/kg (IP) for 1 month, and then evaluated on measures of motor function.  Treatment with both 1 and 5 mg/kg IIPP-1 reversed motor deficits in transgenic mice, compared to vehicle treated transgenic mice.

Consistent with in vitro results, post mortem neuropathological examination of the CNS of these animals treated chronically with IIPP-1 demonstrated a decrease in alpha-synuclein aggregates and an increase in neuronal viability markers (MAP-2 & synaptophysin) in the CNS of transgenic mice compared to vehicle treated transgenic mice.  Taken together, these studies support the further careful evaluation of IIPP-1 as a putative disease modifying treatment for PD/DLB.

Neuropore Therapies, Inc. (NPT) relocates to Torrey Pines Mesa research park

Neuropore Therapies, Inc. has moved from the San Diego Science Center to our new facility on the Road to the Cure in Torrey Pines Mesa.  The new 5000+ sq. ft facility houses expanded biology research space, a new medicinal chemistry lab, and highly functional office and conference spaces.