Elan Pharma International Limited

An2h Discovery Limited

Elan Pharmaceuticals, Inc.

Nysnobio Ireland Dac

E3x Bio, Inc.

Nysnobio Gt Neurology, LLC

Jennifer Johnston

Paul Ross Fatheree

Albert W Garofalo

David Morgans

Brigit Riley

Alfred Goldberg

Colleen Tsui Cutcliffe

The present disclosure provides novel gene therapy constructs comprising a PARK2 gene or activating variant and methods of administering to treat Parkinson's Disease or symptoms thereof.

Gene therapy delivery of Parkin mutants having increased activity to treat Parkinson's disease

The present disclosure is directed to asymmetric triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R, R, R, M, M, M, L, L, and Lare as defined herein. 

Asymmetric triazole benzamide derivatives and the compositions and methods of treatment regarding the same

The present disclosure is directed to triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R, R, R, M, M, M, L, L, and Lare as defined herein. 

Triazole benzamide derivatives and the compositions and methods of treatment regarding the same

The present invention is directed to methods and compositions for activating a Parkin ligase by administering to a subject in need thereof a therapeutically effective amount of a compound that disrupts at least one Parkin ligase zinc finger. The present invention is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase.

Parkin ligase activation methods and compositions

The present invention provides a screen which exploits mechanism-based activity probes that specifically and covalently modify the active site cysteine thiol residue of E3 Ub ligases including, but not limited to the HECT and RBR family. The activity probes are used to screen for activators and inhibitors of E3 Ub ligases, and to interrogate the functional state of E3 Ub ligases in human disease.

Method for identifying modulators of ubiquitin ligases

The invention provides transgenic animals having a transgene comprising a genomic human alpha synuclein segment including six exons, five introns and at least one mutation associated with synucleinopathic disease operably linked to a human alpha synuclein promoter. The transgenic animals have characteristics of synucleinopathic disease including elevated levels of alpha synuclein in the brain, formation of intracellular deposits of alpha synuclein that have at least one, and preferably all features of Lewy bodies, formation of alpha-synuclein fragments, or phosphorylated forms of alpha synuclein, loss of neuronal cells, glial cells or oligodentricytes, impairment of motor function and/or impairment of cognitive function.

Genomic alpha synuclein transgenic animal

The invention provides in vitro, ex vivo, and in vivo assays for Parkin activity, in which Parkin-mediated ubiquitination of a Sept4 protein is measured. The assays may be used to screen for agents that modulate Parkin protein ligase activity.

Parkin substrate and assay

The invention provides to assays for agent useful for treatment of Parkinson's Disease. Included are cell-based assays for agents that modulate the effect of Parkin proteins on proteasome function.

Assay for Parkinson's Disease therapeutics

The invention provides in vitro and cell-based assays for parkin activity, in which parkin-mediated ubiquitination of the S5a subunit of the 26S proteasome is measured, or ubiquitination of troponin 1. The assays may be used to screen for agents that modulate parkin protein ligase activity.

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Mill Valley, CA, United States of America

Jennifer Johnston