Precision editing of granulin mutations that cause frontotemporal dementia

The University of Massachusetts Medical School received a $6.58 million Cooperative Agreement from the National Institute on Aging (Aging Research program, CFDA 93.866) awarded August 15, 2025, with a completion date of July 31, 2029. This award funds development of precision genome editing therapeutic approaches to treat frontotemporal dementia (FTD) caused by granulin (GRN) mutations, specifically targeting the prevalent nonsense mutation C.1477C>T (p.R493X). The research team will assess candidate genome editing strategies using base editing (BE) and prime editing (PE) technologies, initially validating these approaches in patient-derived induced pluripotent stem cell (iPSC)-derived neurons and glial cells, then evaluating efficacy in a humanized GRN-R493X mouse model that recapitulates key FTD disease characteristics.

The award supports development and advancement of both viral vector and novel non-viral delivery strategies to optimize safe and effective central nervous system delivery of the genome editing therapeutic agents. The research aims to establish a maximally effective precision editing approach for GRN-FTD while exploring the feasibility of correcting larger exon segments through prime editing, potentially enabling a single corrective reagent to address multiple mutations affecting the broader FTD patient population. This multidisciplinary effort addresses a significant clinical need, as FTD remains the most common form of presenile dementia before age 60 with no currently available effective treatments.

Abstract

Frontotemporal dementia (FTD) is the most common form of presenile dementia before the age of 60, and no effective treatments are available. 40% of FTD cases are familial and one of the most common genes with FTD-causing mutations is granulin (GRN), which encodes progranulin (pgrn), a secreted regulatory protein. GRN mutations, such as the most prevalent nonsense mutation c.1477C>t (p.R493X), result in pgrn haploinsufficiency, and attempts at developing small molecule, biologic, and gene replacement therapies have proven challenging due to inherent toxicities that result from pgrn overexpression. Precision genome editing strategies to correct the endogenous gene and restore natively regulated progranulin production, even at t (p.R493X). In this proposal, we have assembled an experienced, multidisciplinary team to develop a maximally effective therapeutic editing approach to treat GRN-FTD caused by this mutation. We will assess candidate approaches that employ either be or PE, initially in GRN-FTD patient induced pluripotent stem cell (ipsc)-derived neurons and glial cells to correct GRNR493X, and then compare their effectiveness to prevent disease progression in a humanized GRNR493X mouse that faithfully models some aspects of FTD. Our PE development will also test the feasibility of rewriting larger exon segments, thereby enabling correction of additional mutations from the patient population to be addressed with a single corrective reagent. Safe and effective delivery represents one important challenge in therapeutic genome editing, especially in the central nervous system. We will address this challenge by advancing both viral vector delivery and novel non-viral delivery strategies that we are developing to define the safest and most effective delivery modality for these editing technologies. This work promises to lead to a specific, effective therapeutic intervention for a devastating and currently untreatable form of heritable dementia. Our studies will also advance platform technologies and establish a blueprint for developing clinical genome editing approaches, leveraging these tools for additional mutations that cause FTD and other forms of dementia.