Computationally designed therapy targeting lysosomal function and inflammation in neurodegenerative diseases

Progranulin is a GRN-encoded protein that plays critical lysosomal and anti-neuroinflammatory functions. A therapy that boosts GRN expression would address the root genetic cause (GRN haploinsufficiency) of GRN-subtype frontotemporal dementia (GRN-FTD), a fatal and orphan neurodegenerative disease that affects 3,000-6,000 patients in the US alone. The therapy would also be effective for other neurodegenerative diseases including Alzheimer’s and Parkinson’s diseases. However, no such therapy is available currently. The recent remarkable success of Spinraza/nusinersen for spinal muscular atrophy has clearly demonstrated that antisense oligonucleotide (ASO)-based therapies can be highly effective for neuronal diseases. We have developed three ASOs that can increase the progranulin protein level in a human neuroblastoma cell line by multiple folds. These ASOs have the potential to become effective treatments for GRN-FTD and other neurodegenerative diseases.