Roche (headquartered in Basel, Switzerland) and its US subsidiary Genentech (South San Francisco, CA) have built a significant neuroscience portfolio with focus on neurodegeneration, including Alzheimer's disease and Parkinson's disease. Within the ceramide/sphingolipid pathway space, Roche is developing glucocerebrosidase (GCase) modulators — a complementary approach to GCS inhibitors for targeting the glucosylceramide pathway in GBA-associated PD and broader neurodegeneration.
Roche's strategy centers on the strong genetic and biological link between GBA mutations and PD risk, developing both GCase chaperones (to enhance residual enzyme activity) and small molecule activators (to boost wild-type GCase function) for potential disease modification.
Glucocerebrosidase (GBA1) is a lysosomal hydrolase that cleaves glucosylceramide into ceramide and glucose:
Glucosylceramide + H2O → Ceramide + Glucose
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GCase (GBA1) — deficient in Gaucher disease, reduced in GBA-PD
Roche's lead GCase chaperone is in early clinical development:
Mechanism: Binds to active site of GCase, promoting proper folding and lysosomal trafficking. Increases enzyme activity by 1.5-3x in patient-derived cells.
Development Status:
Preclinical Profile:
AT210 (Structural Analog):
Roche's partnership with Chugai (Japan) provides access to:
| Agent | Type | Target | Indication | Phase | Status |
|---|---|---|---|---|---|
| AT337 | Chaperone | GCase | GBA-PD | Phase 1 | Completed |
| AT337 | Chaperone | GCase | GBA-PD | Phase 1b | Planned |
| AT210 | Activator | GCase | PD (sporadic) | Preclinical | Active |
Roche has pioneered biomarker development for GCase-targeted therapies:
Roche is exploring combinations within the sphingolipid pathway:
| Combination | Rationale |
|---|---|
| GCase chaperone + GCS inhibitor | Dual targeting of glucosylceramide metabolism |
| GCase activator + S1P modulator | Ceramide pathway + neuroinflammation |
| GCase modulator + anti-α-synuclein antibody | Target engagement + protein clearance |
Pavan S et al. Small molecule GCase activators: a new frontier in PD therapy. J Med Chem. 2019. ↩︎