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Editors Selection IGR 11-2

Medical Treatment: Gene Therapy

Comment by Makoto Aihara on:

108419 Matrix metalloproteinase-3 (MMP-3)-mediated gene therapy for glaucoma, O'Callaghan J; Delaney C; O'Connor M et al. et al., Science advances, 2023; 9: eadf6537

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IOP-lowering is indispensable for the treatment of glaucomatous optic nerve damage. The current therapeutic approach mostly depends on eyedrops, which is a big burden for glaucoma patients, especially the elderly. In this respect, gene therapy to lower IOP is an ideal approach to reduce the burden in both patients and medical staffs. O'Callaghan et al. developed a new strategy through infecting corneal endothelial cells by AAV-9 induced MMP3 expression. Based on their previous reports using mice, efficacy and safety profile of MMP3 expression by intracameral injection were biologically optimized and confirmed. Their experiments were well-conducted, and these plausible data supported the sustained reduction of outflow resistance leading to IOP reduction in mouse and non-human primates. Their strategy that MMP3 delivery through aqueous humor to outflow tissues from the non-dividing corneal endothelial cells is excellent and appropriate for the sustainable gene therapy and worth to be proceeded to the clinical trial.

Once the TM cells or Schlemn's canal endothelial cells are damaged and lose their function, the induction of MMP3 may not be effective

Still, there are some challenges for clinical trials. The indication for gene therapy might depend on glaucoma subtype, stage of disease and level of IOP. In glaucoma eyes, many biological factors to increase ECM and tissue scarring such as TGF families or lipid mediators are present in the aqueous humor. It is unknown whether MMP3 induction can overcome the scarring process and recover the function of conventional outflow pathway. Before gene therapy, the function of the outflow pathway should be thoroughly evaluated, although we do not have a useful tool so far. Once the TM cells or Schlemm's canal endothelial cells are damaged and lose their function, the induction of MMP3 may not be effective. Long-term expression of MMP3 may induce unknown adverse events such as chronic inflammation or retino-choroidal changes through the uveoscleral pathway. However, this study is a big advance for the new treatment for IOP reduction in glaucoma.

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