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

Todd Logan; Matthew J. Simon; Anil Rana; Gerald M. Cherf; Ankita Srivastava; Sonnet S. Davis; Ray Lieh Yoon Low; Chi Lu Chiu; Meng Fang; Fen Huang; Akhil Bhalla; Ceyda Llapashtica; Rachel Prorok; Michelle E. Pizzo; Meredith E.K. Calvert; Elizabeth W. Sun; Jennifer Hsiao-Nakamoto; Yashas Rajendra; Katrina W. Lexa; Devendra B. Srivastava; Bettina van Lengerich; Junhua Wang; Yaneth Robles-Colmenares; Do Jin Kim; Joseph Duque; Melina Lenser; Timothy K. Earr; Hoang Nguyen; Roni Chau; Buyankhishig Tsogtbaatar; Ritesh Ravi; Lukas L. Skuja; Hilda Solanoy; Howard J. Rosen; Bradley F. Boeve; Adam L. Boxer; Hilary W. Heuer; Mark S. Dennis; Mihalis S. Kariolis; Kathryn M. Monroe; Laralynne Przybyla; Pascal E. Sanchez; Rene Meisner; Dolores Diaz; Kirk R. Henne; Ryan J. Watts; Anastasia G. Henry; Kannan Gunasekaran; Giuseppe Astarita; Jung H. Suh; Joseph W. Lewcock; Sarah L. DeVos; Gilbert Di Paolo

doi:10.1016/j.cell.2021.08.002

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

Todd Logan, Matthew J. Simon, Anil Rana, Gerald M. Cherf, Ankita Srivastava, Sonnet S. Davis, Ray Lieh Yoon Low, Chi Lu Chiu, Meng Fang, Fen Huang, Akhil Bhalla, Ceyda Llapashtica, Rachel Prorok, Michelle E. Pizzo, Meredith E.K. Calvert, Elizabeth W. Sun, Jennifer Hsiao-Nakamoto, Yashas Rajendra, Katrina W. Lexa, Devendra B. SrivastavaBettina van Lengerich, Junhua Wang, Yaneth Robles-Colmenares, Do Jin Kim, Joseph Duque, Melina Lenser, Timothy K. Earr, Hoang Nguyen, Roni Chau, Buyankhishig Tsogtbaatar, Ritesh Ravi, Lukas L. Skuja, Hilda Solanoy, Howard J. Rosen, Bradley F. Boeve, Adam L. Boxer, Hilary W. Heuer, Mark S. Dennis, Mihalis S. Kariolis, Kathryn M. Monroe, Laralynne Przybyla, Pascal E. Sanchez, Rene Meisner, Dolores Diaz, Kirk R. Henne, Ryan J. Watts, Anastasia G. Henry, Kannan Gunasekaran, Giuseppe Astarita, Jung H. Suh, Joseph W. Lewcock, Sarah L. DeVos, Gilbert Di Paolo

Neurology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Pages (from-to)	4651-4668.e25
Journal	Cell
Volume	184
Issue number	18
DOIs	https://doi.org/10.1016/j.cell.2021.08.002
State	Published - Sep 2 2021

Keywords

GBA
LBPA
galectin-3
lipidomics
lipids
lipofuscin
lysobisphosphatidic acid
lysosome
metabolomics
neurodegenerative disease

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.cell.2021.08.002

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Logan, T., Simon, M. J., Rana, A., Cherf, G. M., Srivastava, A., Davis, S. S., Low, R. L. Y., Chiu, C. L., Fang, M., Huang, F., Bhalla, A., Llapashtica, C., Prorok, R., Pizzo, M. E., Calvert, M. E. K., Sun, E. W., Hsiao-Nakamoto, J., Rajendra, Y., Lexa, K. W., ... Di Paolo, G. (2021). Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic. Cell, 184(18), 4651-4668.e25. https://doi.org/10.1016/j.cell.2021.08.002

Logan, T, Simon, MJ, Rana, A, Cherf, GM, Srivastava, A, Davis, SS, Low, RLY, Chiu, CL, Fang, M, Huang, F, Bhalla, A, Llapashtica, C, Prorok, R, Pizzo, ME, Calvert, MEK, Sun, EW, Hsiao-Nakamoto, J, Rajendra, Y, Lexa, KW, Srivastava, DB, van Lengerich, B, Wang, J, Robles-Colmenares, Y, Kim, DJ, Duque, J, Lenser, M, Earr, TK, Nguyen, H, Chau, R, Tsogtbaatar, B, Ravi, R, Skuja, LL, Solanoy, H, Rosen, HJ, Boeve, BF, Boxer, AL, Heuer, HW, Dennis, MS, Kariolis, MS, Monroe, KM, Przybyla, L, Sanchez, PE, Meisner, R, Diaz, D, Henne, KR, Watts, RJ, Henry, AG, Gunasekaran, K, Astarita, G, Suh, JH, Lewcock, JW, DeVos, SL & Di Paolo, G 2021, 'Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic', Cell, vol. 184, no. 18, pp. 4651-4668.e25. https://doi.org/10.1016/j.cell.2021.08.002

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title = "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.",

keywords = "GBA, LBPA, galectin-3, lipidomics, lipids, lipofuscin, lysobisphosphatidic acid, lysosome, metabolomics, neurodegenerative disease",

author = "Todd Logan and Simon, {Matthew J.} and Anil Rana and Cherf, {Gerald M.} and Ankita Srivastava and Davis, {Sonnet S.} and Low, {Ray Lieh Yoon} and Chiu, {Chi Lu} and Meng Fang and Fen Huang and Akhil Bhalla and Ceyda Llapashtica and Rachel Prorok and Pizzo, {Michelle E.} and Calvert, {Meredith E.K.} and Sun, {Elizabeth W.} and Jennifer Hsiao-Nakamoto and Yashas Rajendra and Lexa, {Katrina W.} and Srivastava, {Devendra B.} and {van Lengerich}, Bettina and Junhua Wang and Yaneth Robles-Colmenares and Kim, {Do Jin} and Joseph Duque and Melina Lenser and Earr, {Timothy K.} and Hoang Nguyen and Roni Chau and Buyankhishig Tsogtbaatar and Ritesh Ravi and Skuja, {Lukas L.} and Hilda Solanoy and Rosen, {Howard J.} and Boeve, {Bradley F.} and Boxer, {Adam L.} and Heuer, {Hilary W.} and Dennis, {Mark S.} and Kariolis, {Mihalis S.} and Monroe, {Kathryn M.} and Laralynne Przybyla and Sanchez, {Pascal E.} and Rene Meisner and Dolores Diaz and Henne, {Kirk R.} and Watts, {Ryan J.} and Henry, {Anastasia G.} and Kannan Gunasekaran and Giuseppe Astarita and Suh, {Jung H.} and Lewcock, {Joseph W.} and DeVos, {Sarah L.} and {Di Paolo}, Gilbert",

note = "Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = sep,

day = "2",

doi = "10.1016/j.cell.2021.08.002",

language = "English (US)",

volume = "184",

pages = "4651--4668.e25",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "18",

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TY - JOUR

T1 - Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

AU - Logan, Todd

AU - Simon, Matthew J.

AU - Rana, Anil

AU - Cherf, Gerald M.

AU - Srivastava, Ankita

AU - Davis, Sonnet S.

AU - Low, Ray Lieh Yoon

AU - Chiu, Chi Lu

AU - Fang, Meng

AU - Huang, Fen

AU - Bhalla, Akhil

AU - Llapashtica, Ceyda

AU - Prorok, Rachel

AU - Pizzo, Michelle E.

AU - Calvert, Meredith E.K.

AU - Sun, Elizabeth W.

AU - Hsiao-Nakamoto, Jennifer

AU - Rajendra, Yashas

AU - Lexa, Katrina W.

AU - Srivastava, Devendra B.

AU - van Lengerich, Bettina

AU - Wang, Junhua

AU - Robles-Colmenares, Yaneth

AU - Kim, Do Jin

AU - Duque, Joseph

AU - Lenser, Melina

AU - Earr, Timothy K.

AU - Nguyen, Hoang

AU - Chau, Roni

AU - Tsogtbaatar, Buyankhishig

AU - Ravi, Ritesh

AU - Skuja, Lukas L.

AU - Solanoy, Hilda

AU - Rosen, Howard J.

AU - Boeve, Bradley F.

AU - Boxer, Adam L.

AU - Heuer, Hilary W.

AU - Dennis, Mark S.

AU - Kariolis, Mihalis S.

AU - Monroe, Kathryn M.

AU - Przybyla, Laralynne

AU - Sanchez, Pascal E.

AU - Meisner, Rene

AU - Diaz, Dolores

AU - Henne, Kirk R.

AU - Watts, Ryan J.

AU - Henry, Anastasia G.

AU - Gunasekaran, Kannan

AU - Astarita, Giuseppe

AU - Suh, Jung H.

AU - Lewcock, Joseph W.

AU - DeVos, Sarah L.

AU - Di Paolo, Gilbert

PY - 2021/9/2

Y1 - 2021/9/2

N2 - 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.

AB - 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.

KW - GBA

KW - LBPA

KW - galectin-3

KW - lipidomics

KW - lipids

KW - lipofuscin

KW - lysobisphosphatidic acid

KW - lysosome

KW - metabolomics

KW - neurodegenerative disease

UR - http://www.scopus.com/inward/record.url?scp=85114012145&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85114012145&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.08.002

DO - 10.1016/j.cell.2021.08.002

M3 - Article

C2 - 34450028

AN - SCOPUS:85114012145

SN - 0092-8674

VL - 184

SP - 4651-4668.e25

JO - Cell

JF - Cell

IS - 18

ER -

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

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Keywords

ASJC Scopus subject areas

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