Methods for treating Parkinson's disease
Inventors
Narain, Niven Rajin • Sarangarajan, Rangaprasad • VISHNUDAS, VIVEK K. • Narain, Paula Patricia • Chaufty, Jeremy • Gesta, Stephane • Roessler, Reinhard
Assignees
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Publication Number
US-11001891-B2
Publication Date
2021-05-11
Expiration Date
Abstract
The present invention provides methods for treating Parkinson's Disease (PD), e.g., PD associated with a genetic mutation in a glucocerebrosidase (GBA) gene or a leucine rich repeat kinase 2 (LRRK2) gene. The methods comprise administering to the subject a modulator, e.g., an inhibitor, of p53-inducible gene 3 (PIG3).
Core Innovation
The invention concerns treating Parkinson’s Disease in a human subject in need thereof by modulating p53-inducible gene 3 (PIG3) (TP53I3). The therapeutic approach focuses on administering a PIG3 inhibitor that inhibits PIG3 by associating with or binding to PIG3 mRNA in a subject having an increased expression level of PIG3.
The disclosed problem is that PD pathology involves increased PIG3 activity and downstream effects including MAPK/p53 signaling, apoptosis, and ROS. The document states a need for methods that treat PD by targeting the PIG3 axis in humans where PIG3 expression is elevated.
The invention further includes therapeutic combinations and patient subgroups, including PD associated with glucocerebrosidase (GCase) through GBA gene mutations and combinations with glucosylceramide synthase (GCS) inhibitors. In this context, GCS inhibitors such as GZ/SAR402671 and GZ667161 are used together with a PIG3 inhibitor for GBA-associated PD, with emphasis on reducing neuronal cell death and PD progression.
Claims Coverage
The document provides three independent claims. Across the independent claims, the main inventive features center on administering a nucleic-acid-based PIG3 inhibitor that inhibits PIG3 by associating with or binding PIG3 mRNA in subjects with increased PIG3 expression, with additional independent coverage for reducing neuronal cell death and for combination therapy with specific GCS inhibitors in a GBA-associated PD setting.
PIG3 mRNA-binding inhibitor for PD treatment with increased PIG3 expression
Administering to a human subject an inhibitor of human p53-inducible gene 3 (PIG3) that inhibits PIG3 by associating with or binding PIG3 mRNA, where the inhibitor comprises a nucleic acid selected from antisense nucleic acid, siRNA, shRNA, and dicer substrate siRNA (DsiRNA), and where the subject has an increased expression level of PIG3, thereby treating Parkinson’s Disease.
PIG3 mRNA-binding inhibitor to reduce neuronal cell death in PD
Administering to a human subject afflicted with Parkinson’s Disease an inhibitor of PIG3 that inhibits PIG3 by associating with or binding to PIG3 mRNA, where the inhibitor comprises a nucleic acid selected from antisense nucleic acid, siRNA, shRNA, and DsiRNA, and where the subject has an increased expression level of PIG3, thereby reducing neuronal cell death and treating Parkinson’s Disease in the subject.
Combination of PIG3 inhibitor and specific GCS inhibitors for GBA-associated PD
Administering in combination to a human subject a PIG3 inhibitor and an inhibitor of human glucosylceramide synthase (GCS), where the PIG3 inhibitor inhibits PIG3 by associating with or binding to PIG3 mRNA and comprises a nucleic acid selected from antisense nucleic acid, siRNA, shRNA, and DsiRNA; where the GCS inhibitor is selected from GZ/SAR402671 and GZ667161; where the Parkinson’s Disease is associated with a genetic mutation in the GBA gene and the subject has an elevated expression level of PIG3, thereby treating Parkinson’s Disease.
Overall, claim coverage is directed to PIG3 inhibition via nucleic-acid-based binding or association to PIG3 mRNA in subjects with increased PIG3 expression, including PD treatment broadly, treatment framed as reducing neuronal cell death, and combination therapy with specified GCS inhibitors for GBA-associated PD.
Stated Advantages
Treating Parkinson’s disease in a subject having increased PIG3 expression.
Reducing neuronal cell death in a subject afflicted with Parkinson’s disease.
Treating Parkinson’s disease in a subject by administering PIG3 inhibitor in combination with a glucosylceramide synthase (GCS) inhibitor selected from GZ/SAR402671 and GZ667161 for GBA-associated PD.
Inhibition or slowing down of PD progression as measured using UPDRS.
Documented Applications
Methods for treating Parkinson’s Disease in a human subject, including PD with increased PIG3 expression.
Methods for reducing neuronal cell death in a human subject afflicted with Parkinson’s Disease.
Combination therapy for Parkinson’s Disease associated with a genetic mutation in the GBA gene using a PIG3 inhibitor together with a GCS inhibitor selected from GZ/SAR402671 and GZ667161.
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