The cou­ple de­vised a cure for an in­her­ited form of blind­ness

A WIFE-ANDHUSBAND RE­SEARCH TEAM CRACKS THE CODE ON GENE THER­APY WITH A NEW TREAT­MENT FOR BLIND­NESS

Smithsonian Magazine - - Features - by Jo­ce­lyn Kaiser

THREE MONTHS AF­TER Misty Lovelace was born, she was al­ready go­ing blind. In first grade she could still read small print, but within a few years her school­books were binders of large-print pages. To nav­i­gate hall­ways, she mem­o­rized the route or de­pended on a teacher or friend. Her sight was “like hav­ing re­ally dark sun­glasses and look­ing through a tun­nel,” she re­calls. In fifth grade, some­one brought in a mo­bile plan­e­tar­ium to show the stu­dents lights rep­re­sent­ing the stars. Misty pre­tended she could seem them.

When she was 12, doc­tors de­ter­mined that Misty’s blind­ness had a ge­netic cause called Le­ber con­gen­i­tal amau­ro­sis (LCA). For­tu­nately, a hus­band-and-wife team at the Univer­sity of Penn­syl­va­nia—Jean Ben­nett and Al­bert Maguire—were test­ing a po­ten­tial cure, and Misty trav­eled from Ken­tucky to take part in the study. A day af­ter the surgery, doc­tors took off her eye patch. “I saw a burst of color. Ev­ery­thing was so much brighter,” she re­calls. For the first time in years, she could clearly see her mother’s face, her grand­mother’s wrin­kles, the fab­ric seams in her stuffed an­i­mals. At home in the back­yard pool one night, she looked up and started scream­ing. “I see th­ese lit­tle lights and they’re all blink­ing. I started to freak,” she re­calls. Her mother rushed out, think­ing chlo­rine was hurt­ing her daugh­ter’s treated eye. Misty could fi­nally see the stars.

Misty’s treat­ment be­came avail­able to the pub­lic dur­ing the past year un­der the name Lux­turna. Its FDA ap­proval in De­cem­ber 2017 was huge news—not only for the 1,000 to 2,000 Amer­i­cans with Misty’s type of LCA, but for peo- ple with other ge­netic dis­eases that could one day be cured through gene ther­apy.

I’d last vis­ited Ben­nett and Maguire ten years ago when they were treat­ing their first pa­tients. This past July, they re­flected on their jour­ney while brunch­ing on their pa­tio in the Philadel­phia sub­urb of Bryn Mawr. Mer­cury, a brown-and-black Bri­ard dog, panted in the heat. Born blind, he was one of the cou­ple’s ear­li­est re­search sub­jects. His mother, Venus, an­other formerly blind dog, was stay­ing cool in­doors.

“There were in­nu­mer­able ob­sta­cles along the way,” said Ben­nett, 63, curled up in a chair with her cof­fee. Maguire, 58, handed me a jar of honey from his bee­hives. He told me his wife de­served credit for fre­quently stay­ing up work­ing late while he was “snor­ing in bed.”

The two met and mar­ried at Har­vard Med­i­cal School—Maguire was be­com­ing an eye sur­geon, and Ben­nett, who also had a PhD in de­vel­op­men­tal bi­ol­ogy, was about to en­ter the new field of gene ther­apy. Work­ing to­gether, the pair showed they could im­prove the vi­sion of mice born with ge­netic blind­ness. In 2000, they tested this on Bri­ard dogs who had been born with de­fec­tive copies of RPE65, the gene af­fected by LCA.

RPE65 is cru­cial for the vis­ual cy­cle in mam­mals. When light hits sen­si­tive pig­ments in the retina, it launches a se­ries of re­ac­tions that make sight pos­si­ble. Ev­ery­one has brief mo­ments when this process fal­ters—for in­stance, af­ter the eye is over­whelmed by a cam­era flash. In healthy eyes, th­ese mo­ments are fleet­ing. But peo­ple who have two de­fec­tive copies of RPE65 don’t re­act to light prop­erly. Over time, the light-sens­ing cells—the rods and cones— die off, caus­ing their vi­sion to dis­ap­pear.

Work­ing with the dogs, the sci­en­tists mod­i­fied an adeno-as­so­ci­ated virus (a small virus that’s harm­less to mam­mals) so it car­ried DNA with nor­mal RPE65. Then they in­jected the virus into one eye of each blind puppy. Within days, the fright­ened dogs who bumped into ob­jects had turned into ac­tive, sighted an­i­mals.

By 2007, it was time to try the pro­ce­dure on peo­ple. The med­i­cal com­mu­nity was still reel­ing from the 1999 death of teenager Jesse Gelsinger in an un­re­lated gene ther­apy study at Penn. Start­ing this new re­search was risky. But Gelsinger had been treated for a metabolic liver dis­ease, and the eye had cer­tain ad­van­tages: It was easy to ac­cess, and only a small area of tis­sue, not the en­tire or­gan, needed to re­ceive the gene. Plus, doc­tors could try the ther­apy in one eye be­fore mov­ing on to the se­cond. (They didn’t ex­pect an is­sue with pa­tients mak­ing an­ti­bod­ies to the virus, since eyes are largely shielded from the body’s im­mune re­sponse.)

Maguire and Ben­nett, to­gether with the Chil­dren’s Hospi­tal of Philadel­phia (CHOP), be­gan test­ing a low dose of this treat­ment in three young adults with RPE65 mu­ta­tions. Maguire in­jected a pea-size drop un­der their reti­nas con­tain­ing bil­lions of RPE65-car­ry­ing viruses. The pa­tients’ vi­sion im­proved—they could read signs and see pat­terns in rugs, and they could read more lines on an eye chart. One Sat­ur­day at home, Ben­nett was look­ing at data on a pa­tient’s pupil con­trac­tion and raced up­stairs to awaken Maguire from a nap. “We were thrilled!” she says.

From there, the team showed they could suc­cess­fully treat the pa­tients’ se­cond eyes. The next step was to seek FDA ap­proval. In 2013, the team founded Spark Ther­a­peu­tics, a biotech firm, to de­velop and fund a larger trial at CHOP and at the Univer­sity of Iowa and carry out other work to get the first U.S. ap­proval for a virus-de­liv­ered treat­ment for a ge­netic dis­ease. “There was no road map, and this was a very heavy lift,” says Kather­ine High, a hema­tol­o­gist and gene ther­apy re­searcher who helped lead the tri­als at CHOP and went on to be­come pres­i­dent of Spark.

Sev­eral chil­dren have now re­ceived Lux­turna as part of their clin­i­cal care. The treat­ment is $850,000 for both eyes. “The cost hor­ri­fies me per­son­ally,” ad­mits Ben­nett. (Nei­ther she nor Maguire prof­its fi­nan­cially from the ther­apy.) High says the price is

steep be­cause “the cur­rent sys­tem is not de­signed for one-time high-value treat­ments.” She notes that drugs for a con­di­tion like he­mo­philia cost as much as $400,000 a year over an en­tire life­time. “One would hope the sys­tem would re­ward ther­a­pies that achieve their ef­fects through a sin­gle treat­ment, but that is not yet the case,” High says.

It’s un­known how long Lux­turna’s ben­e­fits will last, but Maguire says pa­tients treated up to 11 years ago still have sta­ble vi­sion in the se­cond eye, which re­ceived a higher dose than the first. Many of them can now walk without a cane and tell col­ors apart. Those on the younger end of the 4- to 44-year-old age range re­port the most ben­e­fits, since they’d lost fewer pho­tore­cep­tor cells: Kids who couldn’t play out­doors af­ter dark, or ride a bike without help, are now able to do those things. Some of the teenagers are el­i­gi­ble for driver’s li­censes. They are able to play var­sity soc­cer and join the cheer­lead­ing squad. Their so­cial lives blos­somed once they could read friends’ faces.

The cou­ple ac­com­plished all this while rais­ing three chil­dren, now grown. Their house is still dec­o­rated with the kids’ art, along with Maguire’s paint­ings of cows. Their old­est child, Sarah Maguire, is 32 and a post­doc­toral re­searcher at Johns Hop­kins, where she’s tweak­ing the genes of mosquitoes to make them dis­like the smell of hu­mans. She re­calls a fairly nor­mal child­hood, de­spite hav­ing “re­ally quirky” par­ents. “My dad would come home and start danc­ing with the dogs like Pee-wee Her­man,” she says. When she brought in­sect re­search home on a visit last year, Ben­nett ea­gerly equipped a bath­room with a hu­mid­i­fier and heater to keep the bugs alive.

One of th­ese days, Ben­nett and Maguire hope to re­tire and raise cows, sheep or crops—“Berk­shire bud,” Maguire jokes. For now, they’re hard at work at the Cen­ter for Ad­vanced Reti­nal and Oc­u­lar Ther­a­peu­tics, or CAROT, which Ben­nett founded at Penn in 2014. When I vis­ited, re­searchers were mak­ing gene-car­ry­ing viruses for new tri­als. The ex­cite­ment was pal­pa­ble: Lux­turna has paved the way for the FDA to ap­prove a mul­ti­tude of promis­ing treat­ments, not just for the eye but for other or­gans and dis­eases be­ing stud­ied else­where. “There was no path be­fore,” says Ben­nett, “and now there is.”

Misty Lovelace is now 19, and her vi­sion is about 20/64 with glasses. When the sun is shin­ing, she says, “I can do any­thing.” She hopes to soon start her own busi­ness train­ing horses. “I can’t be­lieve it was me,” she says, look­ing back on her role in Ben­nett and Maguire’s study. “It’s just, wow, like hit­ting the lot­tery. They did it. They opened the doors for every­body.”

“I didn’t sleep at all,” says Al­bert Maguire, re­call­ing the night af­ter he and Jean Ben­nett treated their first gene ther­apy pa­tient. The op­er­a­tion was a suc­cess.

LIFESCIENCES Jean Ben­nettand Al­bert Maguire

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