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Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice
Yuri Ciervo, Pietro Rigoni, Linda Bucciarelli, Martina Lombi, Federico Pratesi, Nadia Bologna, Massimo Accardo, Chiara Recchi et al.. Science Translational Medicine, 2026-01-07
Topic: Brain proteins, microglia and lab models
Autologous hematopoietic stem/progenitor cell (HSC)–gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)–related neurodegenerative diseases due to mutations in the PGRN encoding gene ( GRN ), 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 GRN complementary DNA to transduce HSCs that then were transplanted into a Grn −/− mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength ( HLA-DRA gene–based 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 Grn −/− HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in Grn −/− 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.
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APA 7th
Ciervo, Y., Rigoni, P., Bucciarelli, L., Lombi, M., Pratesi, F., Bologna, N., et al. (2026). Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice. Science Translational Medicine. https://doi.org/10.1126/scitranslmed.adw9930
Vancouver
Ciervo Y, Rigoni P, Bucciarelli L, Lombi M, Pratesi F, Bologna N, et al. Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice. Science Translational Medicine. 2026. doi:10.1126/scitranslmed.adw9930. PMID: 41499526.
BibTeX
@article{ciervo2026-41499526,
author = {Ciervo, Yuri and Rigoni, Pietro and Bucciarelli, Linda and Lombi, Martina and Pratesi, Federico and Bologna, Nadia and Accardo, Massimo and Recchi, Chiara and others},
title = {{Restoration of progranulin by engineered hematopoietic stem cell–derived microglia corrects phenotypes of granulin knockout mice}},
journal = {Science Translational Medicine},
year = {2026},
doi = {10.1126/scitranslmed.adw9930},
pmid = {41499526},
url = {https://doi.org/10.1126/scitranslmed.adw9930}
}
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Key findings
- These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.
Why it matters
In mice lacking progranulin, transplanting genetically corrected hematopoietic stem cells restored some progranulin and corrected lipid accumulation, gliosis, and social recognition. This is animal research on progranulin-related conditions such as frontotemporal dementia, so it does not yet show a treatment for Alzheimer's disease in people.
Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Science Translational Medicine) |
| Journal's citation record | 3 / 4 | Science Translational Medicine: journal h-index 365 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Laboratory or animal study (title names “mice”) — scores zero |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 1 / 7 | Cited 4 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | 4 / 6 | Cited 15.8× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 4 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Alessandra Biffi: h-index 44 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | University of Padua: institution h-index 1,158 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 2 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41499526) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 39 / 100 | — |
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