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Drug Development.

Tiffini Voss1, Paulette Triglia1, Yan G Ni2

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|December 26, 2025
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Summary
This summary is machine-generated.

PBFT02 gene therapy shows promise for frontotemporal dementia (FTD) by increasing progranulin levels. Early data suggests potential as a one-time treatment for FTD-GRN, supporting further clinical development.

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Area of Science:

  • Neuroscience
  • Genetics
  • Pharmacology

Background:

  • Frontotemporal dementia (FTD) comprises 25-30% of cases due to autosomal dominant mutations in C9orf72, GRN, or MAPT.
  • No disease-modifying treatments currently exist for FTD, including FTD-GRN.
  • PBFT02 is an investigational therapy targeting FTD-GRN and FTD-C9orf72.

Purpose of the Study:

  • To evaluate the safety and tolerability of PBFT02 gene therapy in a first-in-human clinical trial (upliFT-D).
  • To assess biomarkers of target engagement (progranulin/PGRN), biological activity, and disease progression.
  • To investigate the potential of PBFT02 as a one-time disease-modifying treatment for FTD.

Main Methods:

  • PBFT02, an AAV1 vector delivering the human GRN gene, is administered via intra-cisterna magna (ICM) injection.
  • The upliFT-D trial (NCT04747431) enrolls sequential FTD-GRN and FTD-C9orf72 cohorts.
  • Safety, tolerability, and biomarker data (CSF PGRN, plasma NfL) are collected over a 2-year period with a 3-year extension.

Main Results:

  • PBFT02 increased CSF PGRN levels significantly in all participants, from <3 ng/mL to 13-34 ng/mL at 6-12 months.
  • CSF PGRN increases were stable and durable up to 18 months.
  • Plasma NfL levels remained stable, showing a reduced rate of change compared to natural history data. Two participants experienced SAEs (hepatotoxicity, venous sinus thrombosis).

Conclusions:

  • Interim data from the upliFT-D trial suggests PBFT02 is a potential one-time therapy for FTD-GRN.
  • PBFT02 demonstrates promising safety and biomarker engagement.
  • Further clinical development of PBFT02 for FTD is warranted based on these early findings.