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Carboxy-terminal blockade of sortilin binding enhances progranulin gene therapy, a potential treatment for frontotemporal dementia. | LitMetric

AI Article Synopsis

  • Frontotemporal dementia is often linked to mutations in the progranulin gene, prompting research into therapies like gene therapy and sortilin-blocking drugs.
  • This study tested a modified progranulin that blocks sortilin interactions to see if it would enhance the effectiveness of gene therapy in mice lacking progranulin.
  • The modified progranulin showed improved outcomes, including higher levels of the protein and reductions in neurodegeneration biomarkers compared to the standard gene therapy.

Article Abstract

Unlabelled: Frontotemporal dementia is commonly caused by loss-of-function mutations in the progranulin gene. Potential therapies for this disorder have entered clinical trials, including progranulin gene therapy and drugs that reduce progranulin interactions with sortilin. Both approaches ameliorate functional and pathological abnormalities in mouse models of progranulin insufficiency. Here we investigated whether modifying the progranulin carboxy terminus to block sortilin interactions would improve the efficacy of progranulin gene therapy. We compared the effects of treating progranulin-deficient mice with gene therapy vectors expressing progranulin with intact sortilin interactions, progranulin with the carboxy terminus blocked to reduce sortilin interactions, or GFP control. We found that expressing carboxy-terminally blocked progranulin generated higher levels of progranulin both at the injection site and in more distant regions. Carboxy-terminally blocked progranulin was also more effective at ameliorating microgliosis, microglial lipofuscinosis, and lipid abnormalities including ganglioside accumulation and loss of bis(monoacylglycero)phosphate lipids. Finally, only carboxy-terminally blocked progranulin reduced plasma neurofilament light chain, a biomarker of neurodegeneration, in progranulin-deficient mice. These results demonstrate that modifying the progranulin cargo to block sortilin interactions may be important for increasing the effectiveness of progranulin gene therapy.

One-sentence Summary: The effectiveness of progranulin gene therapy in models of FTD is improved by blocking the protein's carboxy terminus, which prevents sortilin binding.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11430072PMC
http://dx.doi.org/10.1101/2024.09.15.613118DOI Listing

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