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Updated: Jun 28, 2025
Virus Delivery of CRISPR Guides to the Murine Prostate for Gene Alteration
Published on: April 27, 2018
CRISPR editing to mimic porphyria combined with light: A new preclinical approach for prostate cancer
Julian Boutin1,2, Coralie Genevois1,3, Franck Couillaud1,3
1University of Bordeaux, INSERM, UMR 1312, Bordeaux Institute of Oncology, 146 Rue Léo Saignat, 33076 Bordeaux, France.
Abstract:
Thanks to its very high genome-editing efficiency, CRISPR-Cas9 technology could be a promising anticancer weapon. Clinical trials using CRISPR-Cas9 nuclease to ex vivo edit and alter immune cells are ongoing. However, to date, this strategy still has not been applied in clinical practice to directly target cancer cells. Targeting a canonical metabolic pathway essential to good functioning of cells without potential escape would represent an attractive strategy. We propose to mimic a genetic metabolic disorder in cancer cells to weaken cancer cells, independent of their genomic abnormalities. Mutations affecting the heme biosynthesis pathway are responsible for porphyria, and most of them are characterized by an accumulation of toxic photoreactive porphyrins. This study aimed to mimic porphyria by using CRISPR-Cas9 to inactivate UROS, leading to porphyrin accumulation in a prostate cancer model. Prostate cancer is the leading cancer in men and has a high mortality rate despite therapeutic progress, with a primary tumor accessible to light. By combining light with gene therapy, we obtained high efficiency in vitro and in vivo, with considerable improvement in the survival of mice. Finally, we achieved the preclinical proof-of-principle of performing cancer CRISPR gene therapy.
Insights
CRISPR-Cas9 gene therapy successfully mimicked porphyria in prostate cancer cells, causing toxic porphyrin accumulation. This novel approach, combined with light, offers a promising preclinical strategy for directly targeting cancer cells.
Area of Science:
- Biochemistry
- Genetics
- Oncology
Background:
- CRISPR-Cas9 gene editing shows promise for cancer therapy, but direct targeting of cancer cells remains limited.
- Targeting essential metabolic pathways offers a strategy to weaken cancer cells, irrespective of their genetic mutations.
- Porphyria, a metabolic disorder, involves toxic, photoreactive porphyrin accumulation due to heme biosynthesis defects.
Purpose of the Study:
- To mimic a genetic metabolic disorder, porphyria, in prostate cancer cells using CRISPR-Cas9.
- To evaluate the efficacy of targeting the heme biosynthesis pathway for cancer therapy.
- To assess the combined effect of gene therapy and light treatment in a preclinical prostate cancer model.
Main Methods:
- Utilized CRISPR-Cas9 gene editing to inactivate the UROS gene in a prostate cancer model.
- Induced porphyrin accumulation in cancer cells to mimic porphyria.
- Administered combined gene therapy and light treatment to tumor-bearing mice.
- Assessed therapeutic efficacy through in vitro and in vivo experiments, including survival analysis.
Main Results:
- Achieved high CRISPR-Cas9 editing efficiency in vitro and in vivo.
- Demonstrated successful induction of porphyrin accumulation in prostate cancer cells.
- Observed significant improvement in the survival rate of mice treated with the combined therapy.
- Established a preclinical proof-of-principle for cancer CRISPR gene therapy targeting metabolic pathways.
Conclusions:
- Mimicking porphyria via CRISPR-Cas9-mediated UROS inactivation is a viable strategy to target cancer cell metabolism.
- The combination of gene therapy and light offers a potent approach for treating accessible tumors like prostate cancer.
- This study presents a novel preclinical framework for direct cancer cell targeting using gene therapy, paving the way for future clinical applications.
