Table 3.
PGRN-boosting therapies in clinical trials
| Modality | Name | Stage | CTGID | Mechanism of action | Route of administration | Result | References |
|---|---|---|---|---|---|---|---|
| Anti-sortilin antibody | Latozinemab (AL001) | Phase 3 | NCT04374136 | Block lysosomal delivery of PGRN to increase extracellular PGRN | Intravenous (IV) | Under investigation | [232, 236] |
| Anti-sortilin antibody | Latozinemab (AL001) | Phase 2 | NCT03987295 | Block lysosomal delivery of PGRN to increase extracellular PGRN | Intravenous (IV) | Under investigation | [232, 236] |
| Anti-sortilin antibody | Latozinemab (AL001) | Phase 1 | NCT03636204 | Block lysosomal delivery of PGRN to increase extracellular PGRN | Intravenous (IV) | Well tolerated, reduced WBC sortilin, and increased plasma and CSF PGRN in healthy volunteers and aFTD-GRN participants. | [232, 236] |
| Anti-sortilin antibody | AL101 | Phase 2 | NCT06079190 | Block lysosomal delivery of PGRN to increase extracellular PGRN | Intravenous (IV) | Under investigation | No published preclinical data |
| Anti-sortilin antibody | AL101 | Phase 1 | NCT04111666 | Block lysosomal delivery of PGRN to increase extracellular PGRN | Intravenous (IV) or subcutaneous (SC) | Generally safe and well tolerated, and increased plasma and CSF PGRN in healthy volunteers | No published preclinical data |
| GRN gene therapy |
PR006/ LY3884963 |
Phase 1/2 | NCT04408625 | AAV-mediated GRN gene delivery | Intracisterna magna (ICM) | increased CSF PGRN in all patients | [216] |
| GRN gene therapy | PBFT02 | Phase 1/2 | NCT04747431 | AAV-mediated GRN gene delivery | Intracisterna magna (ICM) | Under investigation | [229] |
| GRN gene therapy | AVB-101 | Phase 1/2 | NCT06064890 | AAV-mediated GRN gene delivery | Bilateral intrathalamic infusion | Under investigation | No published preclinical data |
| PGRN protein replacement therapy | DNL593 | Phase 1/2 | NCT05262023 | Brain-penetrant recombinant PGRN biologic | Intravenous (IV) | Under investigation | [210] |
| Alkalizing agent | Amiodarone | Completed (phase 2) | 2011-004571-37 | Upregulate GRN mRNA | Oral | No significant effects on serum PGRN and disease course | [240] |
| HDAC inhibitor | FRM-0334 | Completed (phase 2a) | NCT02149160 | Upregulate GRN mRNA | Oral | Safe and well tolerated, but no effects on plasma and CSF PGRN | [244] |
| Calcium channel blocker | Nimodipine | Completed (Phase 1) | NCT01835665 | Increase secreted PGRN | Oral | Safe and well tolerated, but no effects on plasma and CSF PGRN | [238] |
Abbreviations: WBC, white blood cell