{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T10:17:34Z","timestamp":1777285054415,"version":"3.51.4"},"reference-count":72,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"831","funder":[{"DOI":"10.13039\/501100024091","name":"Orchard Therapeutics","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100024091","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,1,7]]},"abstract":"<jats:p>\n                    Autologous hematopoietic stem\/progenitor cell (HSC)\u2013gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)\u2013related neurodegenerative diseases due to mutations in the PGRN encoding gene (\n                    <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                    ), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human\n                    <jats:italic toggle=\"yes\">GRN<\/jats:italic>\n                    complementary DNA to transduce HSCs that then were transplanted into a\n                    <jats:italic toggle=\"yes\">Grn<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (\n                    <jats:italic toggle=\"yes\">HLA-DRA<\/jats:italic>\n                    gene\u2013based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected\n                    <jats:italic toggle=\"yes\">Grn<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in\n                    <jats:italic toggle=\"yes\">Grn<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adw9930","type":"journal-article","created":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T18:58:20Z","timestamp":1767812300000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":4,"title":["Restoration of progranulin by engineered hematopoietic stem cell\u2013derived microglia corrects phenotypes of granulin knockout mice"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9546-7532","authenticated-orcid":true,"given":"Yuri","family":"Ciervo","sequence":"first","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1653-126X","authenticated-orcid":true,"given":"Pietro","family":"Rigoni","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda","family":"Bucciarelli","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martina","family":"Lombi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7416-9384","authenticated-orcid":true,"given":"Federico","family":"Pratesi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nadia","family":"Bologna","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2501-9264","authenticated-orcid":true,"given":"Massimo","family":"Accardo","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"Recchi","sequence":"additional","affiliation":[{"name":"Orchard Therapeutics, London W6 8PW, UK."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rita","family":"Milazzo","sequence":"additional","affiliation":[{"name":"Altheia Science, Milano 20122, Italy."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6886-1072","authenticated-orcid":true,"given":"Valentina","family":"Poletti","sequence":"additional","affiliation":[{"name":"Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Woman\u2019s and Child Health Department, University of Padova, Padova 35128, Italy."},{"name":"Pediatric Research Institute Citt\u00e0 della Speranza, Padova 35127, 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