Precision Editing of Granulin Mutations that Cause Frontotemporal Dementia - Project Summary 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 <100% editing efficiency, therefore represent a superior therapeutic path. The two best-developed modes of precision editing in vivo are base editing (BE) and prime editing (PE), each with complementary sets of advantages and disadvantages for addressing pathogenic C:G-to-T:A mutations such as GRN c. 1477C>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.
