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Background <p>Chimeric Antigen Receptor (CAR)-T cells therapy has revolutionized the treatment of hematological cancers and are currently redirected towards non-malignant diseases. If correction of the gene defect remains the cornerstone of the treatment of Duchenne Muscular Dystrophy (DMD), the disease-associated fibrosis can limit its efficacy. We thus assessed the effects of eliminating cardiac fibrosis of DMD by CAR-T cells targeting Fibroblast Activation Protein (FAP), a protein strongly expressed by activated fibroblasts.</p> Methods <p>In vitro CAR-T cells expressing both FAP and a green fluorescent probe (GFP) were first co-cultured with FAP + of FAP- target cells to check for FAP-expressing lymphocyte activation. Then, anti-FAP CAR-T cells were intravenously delivered in a dystrophic murine model (D2.<i>mdx</i>), following lymphodepletion, to investigate the kinetics, biodistribution, cardiac functional and anti-fibrotic effects of anti-FAP CAR-T cells compared with control lymphocytes engineered to only express GFP. The mechanism of action at a cellular level was assessed by single-cell RNA-sequencing of harvested hearts.</p> Results <p>In vitro anti-FAP CAR-T cells were successfully activated when co-cultured with FAP + target cells. In a dystrophic murine model (D2.<i>mdx</i>), anti-FAP CAR-T cells, intravenously delivered following lymphodepletion, homed to the heart and skeletal muscles, where they decreased FAP and fibrosis-associated genes. Single-cell RNA-sequencing linked these changes to a decrease in a definite cluster of fibrogenic fibroblasts. Concomitantly, anti-FAP CAR-T cells improved cardiac function compared to control mice injected with GFP-transduced T lymphocytes or bovine serum albumin used as negative controls.</p> Conclusions <p>These results suggest that anti-FAP CAR-T cells could be efficient for mitigating fibrosis and thus complement gene therapy of DMD. More generally, their therapeutic benefits pave the way for potential applications extending to other fibrosis-associated diseases.</p>

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CAR-T cells targeting fibroblast activation protein eliminate pathological fibroblasts and preserve cardiac function in a Duchenne Muscular Dystrophy murine model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月30日

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  • Céline Marigny,
  • Gaëlle Revet,
  • Anne Berger,
  • Morgane Boulch,
  • Nathalie Mougenot,
  • Zhenlin Li,
  • Béatrice Corre,
  • Mégane Lemaitre,
  • Axelle Bois,
  • Clara Castelli,
  • Victor Collombat,
  • Ara Parlakian,
  • Marie-Cécile Perier,
  • Adrian Bot,
  • Jonathan A. Epstein,
  • Peggy Lafuste,
  • Albert Hagege,
  • Haig Aghajanian,
  • Clément Cochain,
  • Philippe Bousso,
  • Onnik Agbulut,
  • Philippe Menasché

摘要

Background

Chimeric Antigen Receptor (CAR)-T cells therapy has revolutionized the treatment of hematological cancers and are currently redirected towards non-malignant diseases. If correction of the gene defect remains the cornerstone of the treatment of Duchenne Muscular Dystrophy (DMD), the disease-associated fibrosis can limit its efficacy. We thus assessed the effects of eliminating cardiac fibrosis of DMD by CAR-T cells targeting Fibroblast Activation Protein (FAP), a protein strongly expressed by activated fibroblasts.

Methods

In vitro CAR-T cells expressing both FAP and a green fluorescent probe (GFP) were first co-cultured with FAP + of FAP- target cells to check for FAP-expressing lymphocyte activation. Then, anti-FAP CAR-T cells were intravenously delivered in a dystrophic murine model (D2.mdx), following lymphodepletion, to investigate the kinetics, biodistribution, cardiac functional and anti-fibrotic effects of anti-FAP CAR-T cells compared with control lymphocytes engineered to only express GFP. The mechanism of action at a cellular level was assessed by single-cell RNA-sequencing of harvested hearts.

Results

In vitro anti-FAP CAR-T cells were successfully activated when co-cultured with FAP + target cells. In a dystrophic murine model (D2.mdx), anti-FAP CAR-T cells, intravenously delivered following lymphodepletion, homed to the heart and skeletal muscles, where they decreased FAP and fibrosis-associated genes. Single-cell RNA-sequencing linked these changes to a decrease in a definite cluster of fibrogenic fibroblasts. Concomitantly, anti-FAP CAR-T cells improved cardiac function compared to control mice injected with GFP-transduced T lymphocytes or bovine serum albumin used as negative controls.

Conclusions

These results suggest that anti-FAP CAR-T cells could be efficient for mitigating fibrosis and thus complement gene therapy of DMD. More generally, their therapeutic benefits pave the way for potential applications extending to other fibrosis-associated diseases.