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Gene therapy ‘cure’ for blindness wanes

Two independent academic groups at the received different doses of vector, 6 showed degeneration was prevented,” says Robin Ali University of Pennsylvania (UPenn) in some improved retinal sensitivity for up to of the UCL Institute of Ophthalmology who Philadelphia and University College London’s three years before decline set in. But compari- led the UK study. (UCL) Institute of Ophthalmology reported son is difficult, even within the same trial, as The UPenn study tested patients ages 16 or long-term results for a gene therapy of Leber’s patients had different levels of blindness and older who had had more than a decade of dis- congenital amaurosis (LCA), a rare form of were treated with different doses, scientists ease progression. “We still don’t know if treat- inherited childhood blindness. Both trials, caution. ing children earlier will provide a longer run testing a single eye in each patient, found that With retinal gene therapy’s longevity now for the therapy,” says Da Cruz. According to efficacy diminished after three or more years, under scrutiny, doubts spilled over to the most Ali, earlier intervention with a more efficient sounding a cautious note amid the technol- advanced LCA treatment, developed by Spark vector to restore RPE65 levels is more likely to ogy’s rapturous renaissance (N. Engl. J. Med. Therapeutics. The Philadelphia-based bio- achieve a sustained benefit. 372, 1887–1897, 2015; N. Engl. J. Med. 372, tech is running a phase 3 trial of SPK-RPE65, The question of age will be addressed 1920–1926, 2015). a similar AAV2-based vector and the same by Spark’s trial, which is targeting patients The trials consisted of early dose-escalation promoter as that in the UPenn study. Spark’s as young as age four. There may be an age studies delivering the RPE65 gene within stock fell 6% in trading the day the data were at which adding back RPE65 (retinal pig- a recombinant adeno-associated virus 2 released. Spark’s treatment for LCA—which ment epithelium (RPE)–specific protein), an (rAAV2) vector by injection into the eye. The appears at birth and causes severe vision loss enzyme necessary to regenerate visual pig- US group used a high expression promoter at an early age—is the farthest along among ment, will not be effective, says Alan Wright of and, by contrast, the UK group used the native the three groups. This news and the recent the University of Edinburgh in Scotland. But, one, which some critics say may not be potent negative phase 2b results from San Diego- the UK study did include two six year olds, enough for clinical benefit. Three patients in based Celladon’s heart failure gene therapy with one showing improvement, and neither the US study—of the 15 enrolled—showed have restrained newly found enthusiasm for study discerned a correlation between age and an improvement measured as visual func- gene therapies (Nat. Biotechnol. 33, 5, 2015). benefit, says Ali. tion and electroretinography for up to three Many moving parts—including pro- One reason for optimism, says Jean Bennett, years after which the benefit diminished. Of moter, dosage and antigenicity—still need professor of ophthalmology at UPenn and sci- the 12 patients tracked in the UK study who to be worked out, but experts remain opti- entific director of Spark’s trial, who was not mistic about gene involved in the recently published studies, is therapy. These that three or more years out, the three UPenn- studies are impor- treated patients still had improved retinal sen- tant milestones, sitivity. demonstrating safe Jeffrey Marrazzo, Spark’s CEO, maintains administration and that their product formulation can maximize stable expression the amount of product delivered to tissue, over several years, and the manufacturing process they employ Nature America, Inc. All rights reserved. America, Inc. © 201 5 Nature says Lyndon Da to remove empty viral capsids will make a dif- Cruz, retinal special- ference in their trial. ist at the Moorfields Amsterdam-based uniQure’s gene therapy is npg Eye Hospital in the only one approved so far and costs $1 mil- London, who was not lion (Nat. Biotechnol. 33, 217–218, 2015). But involved in the trial. this high price is not likely to sit well with pay- One reason for the ers if RPE65 efficacy is short-lived. Marrazzo waning benefit is that says Spark is beginning to conceptualize the although the therapy therapy’s value but data from the ongoing trial can improve how are crucial for the discussion with payers. Allan viable photoreceptor Marchington, of Apposite Capital, a London- cells function, the based investment firm, says there is value in current vectors likely improving a child’s sight for even three years cannot rescue already but more data are needed before the health damaged photore- economics of this gene therapy will crystallize. ceptor cells. “We According to Da Cruz, targeting rare diseases think the improve- is only the beginning—lower prices will be fea- ments diminished sible when a single gene therapy can be shown because the loss of to modify diseases affecting larger populations, photoreceptor cells such as macular degeneration, even if the treat- Andrzej Wojcicki / Science Source Andrzej Wojcicki continued. There ment does not result in a cure. Gene therapy’s therapeutic payload may need topping up. was no evidence that Anna Azvolinsky New York

678 volume 33 NUMBER 7 JULY 2015 nature biotechnology