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Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results
Sevigny J, Uspenskaya O, Heckman LD, Wong LC, Hatch DA, Tewari A, Vandenberghe R, Irwin DJ et al.. Nature medicine, 2024-05-14
Topic: Brain proteins, microglia and lab models
GRN mutations cause progranulin haploinsufficiency, which eventually leads to frontotemporal dementia (FTD-GRN). PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector. In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates.
Key findings
- PR006 is an investigational gene therapy delivering the granulin gene (GRN) using an adeno-associated virus serotype 9 (AAV9) vector.
- In non-clinical studies, PR006 transduced neurons derived from induced pluripotent stem cells of patients with FTD-GRN, resulted in progranulin expression and improvement of lipofuscin, lysosomal and neuroinflammation pathologies in Grn-knockout mice, and was well tolerated except for minimal, asymptomatic dorsal root ganglionopathy in non-human primates.
- We initiated a first-in-human phase 1/2 open-label trial.
- Here we report results of a pre-specified interim analysis triggered with the last treated patient of the low-dose cohort (n = 6) reaching the 12-month follow-up timepoint.
Why it matters
This first-in-human phase 1/2 trial tested PR006, an investigational gene therapy delivering the granulin gene using an AAV9 vector, in patients with frontotemporal dementia caused by GRN mutations. Non-clinical studies showed the therapy transduced patient-derived neurons and improved pathologies in mice, and the trial is ongoing to assess safety and tolerability.
Study details
- Study designclinical trial
- Evidence strengthModerate
How this study scored 71/100
Published in a top-tier journal, and it is a mid-stage phase 2 trial. Scored zero for sample size, effect reported and randomised / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 10 / 10 | Tier 1 — top-tier general journal (Nature medicine) |
| Journal's citation record | 4 / 4 | Nature Medicine: journal h-index 763 (OpenAlex, 2026-10-29) |
| Study design | 8 / 12 | A mid-stage phase 2 trial (from PubMed type “Clinical Trial, Phase II”) |
| Strength of evidence | 3 / 5 | Rated “moderate” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2024 — within 3 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 | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 4 / 7 | Cited 70 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 17.5 citations a year over 4 year(s) since 2024 |
| Impact for its field and year | 4 / 6 | Cited 17.2× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 2 / 6 | Cited by 7 other studies in this library |
| Still being cited | 3 / 4 | Cited 70 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Franz F. Hefti: h-index 89 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Centre National de la Recherche Scientifique: institution h-index 2,511 (OpenAlex) |
| Multi-centre collaboration | 3 / 3 | OpenAlex lists 11 institution(s) in 5 countries |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 38745011) |
| Free to read | 2 / 2 | Free to read |
| Total | 71 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1038/s41591-024-02973-0
- PubMed: 38745011
- Original source →
- Free full text: Nature Medicine →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Sevigny, J., Uspenskaya, O., Heckman, L. D., Wong, L. C., Hatch, D. A., Tewari, A., et al. (2024). Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results. Nature medicine. https://doi.org/10.1038/s41591-024-02973-0
Vancouver
Sevigny J, Uspenskaya O, Heckman LD, Wong LC, Hatch DA, Tewari A, et al. Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results. Nature medicine. 2024. doi:10.1038/s41591-024-02973-0. PMID: 38745011.
BibTeX
@article{sevigny2024-38745011,
author = {Sevigny, J. and Uspenskaya, O. and Heckman, L. D. and Wong, L. C. and Hatch, D. A. and Tewari, A. and Vandenberghe, R. and Irwin, D. J. and others},
title = {{Progranulin AAV gene therapy for frontotemporal dementia: translational studies and phase 1/2 trial interim results}},
journal = {Nature medicine},
year = {2024},
doi = {10.1038/s41591-024-02973-0},
pmid = {38745011},
url = {https://doi.org/10.1038/s41591-024-02973-0}
}
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