ArticleMolecular therapy : the journal of the American Society of Gene Therapy2019
AAV-Mediated Progranulin Delivery to a Mouse Model of Progranulin Deficiency Causes T Cell-Mediated Toxicity.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
42 citing papers in PubMed, 58 citations in OpenAlex.
- Distribution of transgene in the rodent choroid plexus after intracerebroventricular injection of adeno-associated virus.Fluids and barriers of the CNS · 2026Article
- Progranulin: Dose-dependent neurotoxicity.Neural regeneration research · 2026Article
- Selective neuronal restoration of progranulin does not prevent the frontotemporal dementia like-phenotype of progranulin knockout mice.Journal of neuroinflammation · 2026Article
- The first report of ceroid lipofuscinosis type 11 in China: a novel mutation of GRN and updated clinical review.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Review
- New Diagnostic and Therapeutic Targets for Spinal Cord Injury: GRN Gene.Journal of cellular and molecular medicine · 2025Article
- The role of endolysosomal progranulin and TMEM106B in neurodegenerative diseases.Molecular neurodegeneration · 2025Review
- TFEB overexpression alleviates autophagy-lysosomal deficits caused by progranulin insufficiency.Scientific reports · 2025Article
- Efficacy and preliminary safety assessment of EXG001-307 AAV gene therapy for spinal muscular atrophy.Molecular therapy. Methods & clinical development · 2025Article
- Harnessing human iPSC-microglia for CNS-wide delivery of disease-modifying proteins.Cell stem cell · 2025Article
- Is it possible to prevent excessive synaptic pruning in schizophrenia? Possibilities and limitations.Frontiers in synaptic neuroscience · 2025Review
- The promise of gene therapy in common types of dementia.BioImpacts : BI · 2025Review
- Selective neuronal expression of progranulin is sufficient to provide neuroprotective and anti-inflammatory effects after traumatic brain injury.Journal of neuroinflammation · 2024Article
- CNS-wide repopulation by hematopoietic-derived microglia-like cells corrects progranulin deficiency in mice.Nature communications · 2024Article
- Upstream lipid and metabolic systems are potential causes of Alzheimer's disease, Parkinson's disease and dementias.The FEBS journal · 2024Review
- Identifying and Diagnosing TDP-43 Neurodegenerative Diseases in Psychiatry.The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry · 2024Review
- Increased circulating progranulin is not sufficient to induce cardiac dysfunction or supraventricular arrhythmia.Scientific reports · 2023Article
- AAV-iScience · 2023Article
- Preclinical Interventions in Mouse Models of Frontotemporal Dementia Due to Progranulin Mutations.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2023Review
- A short hepatitis C virus NS5A peptide expression by AAV vector modulates human T cell activation and reduces vector immunogenicity.Gene therapy · 2022Article
- Neuroimmune dysfunction in frontotemporal dementia: Insights from progranulin and C9orf72 deficiency.Current opinion in neurobiology · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Adeno-associated virus-mediated gene replacement is emerging as a safe and effective means of correcting single-gene mutations affecting the CNS. AAV-mediated progranulin gene (GRN) delivery has been proposed as a treatment for GRN-deficient frontotemporal dementia and neuronal ceroid lipofuscinosis, and recent studies using intraparenchymal AAV-Grn delivery to brain have shown moderate success in histopathologic and behavioral rescue in mouse models. Here, we used AAV9 to deliver GRN to the lateral ventricle to achieve widespread expression in the Grn null mouse brain. We found that, despite a global increase in progranulin, overexpression resulted in dramatic and selective hippocampal toxicity and degeneration affecting neurons and glia. Hippocampal degeneration was preceded by T cell infiltration and perivascular cuffing. GRN delivery with an ependymal-targeting AAV for selective secretion of progranulin into the cerebrospinal fluid similarly resulted in T cell infiltration, as well as ependymal hypertrophy. Interestingly, overexpression of GRN in wild-type animals also provoked T cell infiltration. These results call into question the safety of GRN overexpression in the CNS, with evidence for both a region-selective immune response and cellular proliferative response. Our results highlight the importance of careful consideration of target gene biology and cellular response to overexpression prior to progressing to the clinic.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.