Abstract Details

Title ASIC1 Blockade in Primary Progressive Multiple Sclerosis: Evidence of Neuroprotection with Amiloride

Topic MS and Related Diseases

Presentation(s) S31 - (-)

Poster/Presentation
Number 002

Objective

Background Neurodegeneration is a major cause of permanent disability in multiple sclerosis (MS) yet current therapies target predominantly inflammatory mechanisms resulting in an unmet need for effective neuroprotective agents. Converging evidence from basic science suggests that blockade of acid sensing ion channel1 (ASIC1) through amiloride, a potassium sparing diuretic, has neuro- and myelo-protective effects in experimental models of MS. However this strategy remains untested in MS patients.

Design/Methods We tested the neuroprotective effect of amiloride in a cohort of 14 PPMS patients using high resolution T1 weighted and diffusion tensor imaging to assess brain atrophy and neuroaxonal integrity. PPMS patients underwent serial MRI scans before (pre-treatment phase) and during (treatment phase) amiloride treatment over a period of 3 years.Expanded Disability Status Scale (EDSS) were obtained at the same time points as the MRI. We compared the rate of changes in the pre-treatment vs. amiloride treatment phases.

Results In PPMS patients, we observed a significant reduction in normalized annual rate of whole brain volume change during the treatment phase, compared to the pre-treatment phase (p=0.018 corrected). This was paralleled by a significant reduction in diffusion indices of tissue damage within major, clinically relevant white matter (corpus callosum, cortico-spinal tract) and deep grey matter (thalamus) structures during the treatment phase (p=0.02 corrected). Consistent with imaging results the mean increase in EDSS was greater in the pre-treatment (0.71767) compared to the treatment phase (0.25).

Conclusions Our results extend evidence of the contribution of ASIC1 to neurodegeneration and suggest that amiloride may exert neuroprotective effect in progressive MS patients. This pilot study is the first translational study on neuroprotection targeting ASIC1 in patients and supports further investigation of amiloride as a novel neuroprotective drug in MS. Other neurodegenerative conditions may also benefit from these findings.

Authors/Disclosures
Tarunya Arun PRESENTER	No disclosure on file
Valentina Tomassini, MD (University G. d'Annunzio of Chieti-Pescara)	No disclosure on file
Emilia Sbardella (Policlinico Umberto I)	No disclosure on file
	No disclosure on file
	No disclosure on file
Maria I. Leite, MD (Nuffield Department of Clinical Neurosciences - University of Oxford)	The institution of Dr. Leite has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. The institution of Dr. Leite has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Horizon / Amgen. The institution of Dr. Leite has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. The institution of Dr. Leite has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Viela/Horizon/Amgen. The institution of Dr. Leite has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB. The institution of Dr. Leite has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Amgen. The institution of Dr. Leite has received research support from Non-Profit Organization - Myaware. The institution of Dr. Leite has received research support from UCB - Ra Pharma. The institution of Dr. Leite has received research support from Non-Profit Organization - Muscular Dystrophy UK.
	No disclosure on file
Matt Craner, MD, PhD (Frimley Park Hospital NHS Foundation Trust)	Matt Craner, MD, PhD has nothing to disclose.
David J. Burn, MD (Regional Neuroscience Centre)	No disclosure on file
	No disclosure on file
	No disclosure on file
Jacqueline Palace (John Radcliff Hospital Oxford Univeristy Hospitals Trust)	Dr. Palace has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Merck Serono, Medimmune, Argenx, Janssen, AMgen, UCB, Roche, Novartis, Amplo, Alexion, . Dr. Palace has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx, Sanofi. Dr. Palace has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Roche, UCB, Alexion, Amgen. Dr. Palace has stock in Astra Zenica. The institution of Dr. Palace has received research support from Roche, AMPLO, Alexion, UCB,. argenx, amgen. Dr. Palace has received intellectual property interests from a discovery or technology relating to health care.

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