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Abstract Details

MIN-102 (leriglitazone), a Brain Penetrant PPAR gamma Agonist, Decreases Neuroinflammation and Neurodegeneration and Promotes Re-Myelination in Preclinical Models of X-linked Adrenoleukodystrophy (X-ALD)
General Neurology
S51 - General Neurology: Models of Clinical Care and Disease (1:12 PM-1:24 PM)
002
Leriglitazone is a brain penetrant, small molecule, which selectively acts through the peroxisome proliferator-activated receptor gamma and exerts several pleiotropic effects making it an ideal therapeutic approach towards the different pathophysiological alterations of X-linked adrenoleukodystrophy (X-ALD). In the central nervous system X-ALD presents as two main phenotypes: the adult form adrenomyeloneuropathy (AMN) - a progressive spinal cord axonopathy - and the aggressive cerebral inflammatory form (cALD). In this study, we show that leriglitazone can cross intact or altered blood-brain barrier (BBB) and exhibits efficacy in multiple preclinical models relevant for both phenotypes of X-ALD.

To investigate the preclinical efficacy of a new investigational drug, leriglitazone, in models of neurodegeneration, neuroinflammation and demyelination/remyelination relevant to X-ALD and to other neuroinflammatory conditions.

Single Abcd1 and double Abcd1/Abcd2 knockouts were used as preclinical models of AMN. The widely used Experimental Autoimmune Encephalomyelitis and the Cuprizone mice models were used to study the potential effects of leriglitazone in neuroinflammation, such as it occurs in cALD, and in enhancing remyelination respectively.  Several in vitro models including a BBB transwell system and human cells from X-ALD patients were used to investigate the brain penetration of leriglitazone and its protective effects in macrophages, neurons, microglia, astrocytes and oligodendrocytes. 

Leriglitazone decreased microglia activation, reversed pro-inflammatory status, prevented early pathological stages that lead to BBB disruption, promoted remyelination by increasing myelination, myelin debris clearance and oligodendrocyte survival. Importantly, leriglitazone influenced progression of neurological disability and reverted motor dysfunction

The preclinical data indicate that leriglitazone is a promising therapeutic approach to treat both CNS phenotypes of X-ALD, AMN and cALD, as well as other neuroinflammatory and/or neurodegenerative diseases.  Lerigltazone is currently in a phase 2/3 clinical trial in AMN in Europe and US, and in two phase 2 trials, in cALD and Friedreich´s Ataxia respectively, in Europe.

 

Authors/Disclosures
Sonia Poli
PRESENTER
No disclosure on file
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Patricia Musolino, MD, PhD Dr. Musolino has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Minoryx Pharmaceuticals. Dr. Musolino has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Altas Venture Capital. Dr. Musolino has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for IONIS Pharmaceuticals . Dr. Musolino has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vertex. The institution of Dr. Musolino has received research support from National Institute of Health-NINDS-R01. The institution of Dr. Musolino has received research support from Angea Biotherapeutics. The institution of Dr. Musolino has received research support from Minoryx Pharmaceuticals. Dr. Musolino has received publishing royalties from a publication relating to health care.
Marc Martinell Marc Martinell has received personal compensation for serving as an employee of Minoryx Therapeutics. Marc Martinell has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Minoryx Therapeutics. Marc Martinell has stock in Minoryx Therapeutics. Marc Martinell has received intellectual property interests from a discovery or technology relating to health care.
Pilar Pizcueta Pilar Pizcueta has received personal compensation for serving as an employee of Minoryx Therapeutics SL.