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Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

ABSTRACT: GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn^-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn^-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn^-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn^-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.

SUBMITTER: Logan T

PROVIDER: S-EPMC8489356 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

Logan Todd T Simon Matthew J MJ Rana Anil A Cherf Gerald M GM Srivastava Ankita A Davis Sonnet S SS Low Ray Lieh Yoon RLY Chiu Chi-Lu CL Fang Meng M Huang Fen F Bhalla Akhil A Llapashtica Ceyda C Prorok Rachel R Pizzo Michelle E ME Calvert Meredith E K MEK Sun Elizabeth W EW Hsiao-Nakamoto Jennifer J Rajendra Yashas Y Lexa Katrina W KW Srivastava Devendra B DB van Lengerich Bettina B Wang Junhua J Robles-Colmenares Yaneth Y Kim Do Jin DJ Duque Joseph J Lenser Melina M Earr Timothy K TK Nguyen Hoang H Chau Roni R Tsogtbaatar Buyankhishig B Ravi Ritesh R Skuja Lukas L LL Solanoy Hilda H Rosen Howard J HJ Boeve Bradley F BF Boxer Adam L AL Heuer Hilary W HW Dennis Mark S MS Kariolis Mihalis S MS Monroe Kathryn M KM Przybyla Laralynne L Sanchez Pascal E PE Meisner Rene R Diaz Dolores D Henne Kirk R KR Watts Ryan J RJ Henry Anastasia G AG Gunasekaran Kannan K Astarita Giuseppe G Suh Jung H JH Lewcock Joseph W JW DeVos Sarah L SL Di Paolo Gilbert G

Cell 20210826 18

GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn<sup>-/-</sup> mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn<sup>-/-</sup> brains also showed an age-dependent, secondary storage of glucoc ...[more]

PMID: 34450028

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Project description:BackgroundFrontotemporal lobar degeneration (FTLD) is a devastating and progressive disorder, and a common cause of early onset dementia. Progranulin (PGRN) haploinsufficiency due to autosomal dominant mutations in the progranulin gene (GRN) is an important cause of FTLD (FTLD-GRN), and nearly a quarter of these genetic cases are due to a nonsense mutation. Premature termination codons (PTC) can be therapeutically targeted by compounds allowing readthrough, and aminoglycoside antibiotics are known to be potent PTC readthrough drugs. Restoring endogenous PGRN through PTC readthrough has not previously been explored as a therapeutic intervention in FTLD.MethodsWe studied whether the aminoglycoside G418 could increase PGRN expression in HEK293 and human induced pluripotent stem cell (hiPSC)-derived neurons bearing the heterozygous S116X, R418X, and R493X pathogenic GRN nonsense mutations. We further tested a novel substituted phthalimide PTC readthrough enhancer in combination with G418 in our cellular models. We next generated a homozygous R493X knock-in hiPSC isogenic line (R493X-/- KI), assessing whether combination treatment in hiPSC-derived neurons and astrocytes could increase PGRN and ameliorate lysosomal dysfunction relevant to FTLD-GRN. To provide in vivo proof-of-concept of our approach, we measured brain PGRN after intracerebroventricular administration of G418 in mice expressing the V5-tagged GRN nonsense mutation R493X.ResultsThe R418X and R493X mutant GRN cell lines responded to PTC readthrough with G418, and treatments increased PGRN levels in R493X-/- KI hiPSC-derived neurons and astrocytes. Combining G418 with a PTC readthrough enhancer increased PGRN levels over G418 treatment alone in vitro. PGRN deficiency has been shown to impair lysosomal function, and the mature form of the lysosomal protease cathepsin D is overexpressed in R493X-/- KI neurons. Increasing PGRN through G418-mediated PTC readthrough normalized this abnormal lysosomal phenotype in R493X-/- KI neuronal cultures. A single intracerebroventricular injection of G418 induced GRN PTC readthrough in 6-week-old AAV-GRN-R493X-V5 mice.ConclusionsTaken together, our findings suggest that PTC readthrough may be a potential therapeutic strategy for FTLD caused by GRN nonsense mutations.

Dataset Information

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

Publications

Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.

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