Date Posted: 04 November 2009
A gene therapy treatment of 12 patients between the ages of 8-44 years suffering RPE65-associated Leber's Congenital Amaurosis (LCA) has been shown to improve vision in all participants. The report noted that "patients had at least a 2 log unit increase in pupillary light responses and an 8 year old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals". For observers of the field of gene therapy the report represents a major milestone in the clinical use of the technology. LCA is one of the most severe forms of childhood blinding disorders arising from mutations in any one of 13 genes. Type II or RPE65-associated LCA accounts for about 6% of cases and, as there is no treatment, the condition inevitably progresses to severe visual impairment with total blindness occurring between the third and fourth decade of life.
The 2-year study using a virally delivered copy of the RPE65 gene demonstrated good tolerability, safety and a sustained improvement in both subjective and objective measurements of vision. The AAV delivered human RPE65 gene containing a chicken βâ€"actin promoter and an optimised Kozak sequence was sub-retinally injected in low-, medium- and high- doses of 1.5X1010, 4.8X1010 and 1.5X1011 vector genomes, respectively. All 12 patients treated reported improved vision under dim light conditions 2 weeks after surgery. A stronger pupillary light reflex, a reduction in nystagmus and an improvement in the subjective assessment of the children's ability to walk all pointed to a benefical effect of the treatment.
Substantial visual field improvements were reported in participants aged 8, 9 and 10 years of age suggesting a clear correlation with the amount of salvageable retina targeted. The ability of treated participants to navigate an obstacle course independently and accurately under dim-light vision was one of the most encouraging outcome measurements used, resonant of Gerald Fishman's theorem that an optimal end-point in such trials should be an unsophisticated quantification of shin bruising. The authors of the study concluded that "although young patients had better visual function at baseline than did older individuals, they also had the greatest overall improvement in vision" and that "the visual recovery noted in the children confirms the hypothesis that efficacy will be improved if treatment is applied before retinal degeneration has progressed" [www.thelancet.com, published online Oct 24, 2009 DOI:10.1016/S0140-6736(09)61836-5].
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