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Matthew Hirsch, Richard Samulski; AAV Gene Therapy for MPS1 Corneal Clouding. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):260.
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© ARVO (1962-2015); The Authors (2016-present)
Cell therapy using unrelated donor umbilical cord blood transplantation after myeloablative chemotherapy has extended the lifespan of MPS1 patients, however, >30% have progressive corneal-associated blindness. It is evident that the reason for the progressive eye disease in these treated children is due to the failure of the IDUA enzyme produced by donor cells to reach the cornea. Given the high prevalence of corneal clouding and the high degree of cornea transplant rejection in MPS1 children, these experiments investigate ocular gene therapy for MPS1-associated corneal clouding.<br />
AAV vector transduction experiments were performed using a GFP reporter or codon optimized IDUA cDNA in MPS1 patient fibroblasts and in mouse and human corneas. <br />
The results identify a chimeric AAV serotype 8 capsid and a synthetic inverted terminal repeat (ITR) sequence enhanced for cornea transduction following intrastromal injection. Widespread transduction was observed throughout the stroma in a volume dependent manner. Optimization of the AAV-IDUA vector cassette resulted in dose-dependent restoration (and overexpression) of functional IDUA in different MPS1 patient fibroblasts. Histology experiments in WT human corneas identified normal IDUA levels and, separately, superphysiological IDUA abundance following AAV-IDUA transduction ex vivo. <br />
This work has generated a potent IDUA vector cassette and a human cornea delivery reagent using a chimeric AAV capsid and a synthetic AAV ITR sequence. In particular, this reagent proved effective for functional IDUA delivery in MPS1 patient fibroblasts, as well as in human corneas. Current experiments are addressing safety and efficacy concerns in MPS1 animal models towards correction of corneal clouding in MPS1 patients receiving bone marrow therapy. As there have been over 70 AAV clinical trials in the eye, and the potential for compassionate use in the ocular compartment of MPS1 children, the likelihood of developing a successful therapeutic is high. Although this effort initially targets the most common ocular abnormality in MPS1 patients, it will set precedence for the extrapolation of AAV-IDUA restoration to the retina as well. <br /> <br />
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