Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Cell Biology
• Molecular Biology

Background:

• Reduced progranulin (PGRN) levels are implicated in frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).
• Sortilin (SORT1) mediates PGRN uptake and degradation; inhibiting SORT1 increases extracellular PGRN.
• GSK5862611 is an anti-SORT1 antibody designed to boost extracellular PGRN levels.

Purpose of the Study:

• To evaluate if enhancing PGRN levels with GSK5862611 can reverse phenotypes associated with the TDP43 G298S risk variant.
• To assess the therapeutic potential of anti-Sortilin antibodies in cellular models of neurodegenerative disease.

Main Methods:

• Human induced pluripotent stem cell (hiPSC)-derived motor neurons and astrocytes with the TDP43 G298S risk variant were used.
• Cells were co-cultured with wild-type or GRN-edited microglia and treated with GSK5862611, isotype control, or recombinant PGRN.
• Assessed impacts on neurite length, TDP43 mislocalization, and levels of PGRN, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

Main Results:

• Recombinant PGRN and GSK5862611 treatment rescued neurite length loss and TDP43 mislocalization in motor neurons.
• GSK5862611 increased extracellular PGRN and reduced TDP43 mislocalization in a dose-dependent manner in tricultures.
• GSK5862611 also reduced NfL and GFAP levels in TDP43 G298S cellular models.

Conclusions:

• Blocking Sortilin receptors with GSK5862611 increases extracellular PGRN, reduces TDP43 mislocalization, and lowers NfL/GFAP levels.
• These findings support the potential of anti-Sortilin antibodies as a therapeutic strategy for ALS and related TDP43 proteinopathies.