How rare sheep from biblical times may help kids with a deadly genetic disease

Two newborn lambs mysteriously fell sick, quickly regressed and died in the spring of 1999 on a Texas ranch named for Saint Jude, the Roman Catholic patron of lost causes.

That launched an odyssey for Fred and Joan Horak, retirees breeding rare sheep traced to the biblical era and named after the Jewish patriarch Jacob, who is described in the Bible as raising similar sheep. Their quest to discover why the lambs died ultimately helped advance research into Tay-Sachs, a genetic disease that affects humans as well as animals.

Now scientists are fine-tuning new therapy that has extended life spans in diseased Jacob sheep and in cats. And the Tay-Sachs Gene Therapy Consortium plans to seek federal approval to begin clinical trials on humans next year.

Scientists and advocacy groups say the therapy represents the best hope for fighting the disease, which usually kills children by age 5 and for which there is no cure.

It would be a treatment three millennia in the making, dating to the domestication of a breed that has an unusual look -- some of them have four horns, some have six -- and a genetic defect that is also found in people. But the modern breakthrough required the Horaks' tenacity, scientists connecting the dots and cutting-edge medicine.

"It's been a long journey," said Miguel Sena-Esteves, head of the consortium of eight scientists and doctors that developed the treatment.

Tay-Sachs is caused when the body does not produce enough of an enzyme, Hexosaminidase A (HexA), which recycles toxins from the body. The toxins build, progressively destroying the nervous system. The earlier the onset in children, the quicker it kills.

Consortium researchers use a re-engineered virus to introduce the gene that produces HexA, said Sena-Esteves, a scientist at the University of Massachusetts Medical School who specializes in gene therapy for neurological diseases. The virus is a cargo vessel, its genetic material removed and replaced with a concentrated dose of the HexA gene as its payload.

Acting like a bucket brigade, healthy cells pass along the gene until, in effect, they soak cells lacking HexA, enabling them to produce the crucial enzyme.

The experimental therapy has extended the lives of cats, which have a similar genetic defect, from an average of four months to 18 months, the consortium reports. Some lived past age 2, the consortium reports.

Outcomes are less dramatic with Jacob sheep: a 50 percent life span extension, from an average of nine months to 14.3 months. But the sheep are especially valuable in the search for a human cure. The Tay-Sachs gene in Jacob sheep is an 86 percent DNA match with the human HexA gene.

The consortium plans to seek federal approval for human trials while refining the gene therapy and methods for administering it. Advocates also will push for routine newborn screening nationwide.

"There is no question now the disease can be treated," said Doug Martin, a consortium member whose work involving felines at the Scott-Ritchey Research Center at Auburn University in Alabama expanded in 2010 to include Jacob sheep. "It's not perfect, but it can be improved."

The Auburn treatment is administered by precision-guided injections through holes in the skull, which succeeded in getting therapy beyond what is called the blood-brain barrier. The goal is to develop an IV drip that fully treats the central nervous system by providing sufficient doses to both the brain and the blood system.

"The treatment is in the first generation," said Susan Kahn, executive director of the National Tay-Sachs and Allied Diseases Association (NTSAD), which helps fund research by the consortium and other scientists exploring different treatment methods. "But I think the promise for the future is very positive."

Tay-Sachs was identified in humans in the 1880s. Research on Tay-Sachs in animals dates to the 1960s, including at Auburn's Scott-Ritchey Center.

Although Tay-Sachs is deadly in children, a form of the disease that appears in early adulthood is not always fatal, though it causes severe neurological problems. The HexA gene defect occurs throughout the general population, but highest-risk groups include Ashkenazi Jews, French Canadians and American Cajuns. People of Irish-British Isles descent carry a moderately high risk, according to NTSAD.

Both parents must be carriers to pass on the disease. Each of their children has a 25 percent chance of developing symptoms. Each also carries a 50 percent chance of being a carrier without developing symptoms, and a 25 percent chance of not inheriting the defect.

The advances are a glimmer of hope, said Shari Ungerleider, whose first son, Evan, died from Tay-Sachs in 1998 at age 4 1/2.

"We were told, 'There's nothing now that will help your child and there probably won't in your lifetime, either,' " said Ungerleider, who became active in Tay-Sachs education and is a past president of NTSAD. "Now I strongly believe in my life we will see a child receive treatment."

Shari Ungerleider and her husband, Jeff, knew something was wrong. At 6 months, Evan was not sitting up, much less trying to crawl. He still had that exaggerated startle reflex common in newborns.

"It being our first child, we were not sure what was going on," Ungerleider said.

The couple, Ashkenazi Jews, knew they were in the highest-risk group for Tay-Sachs. But after a pre-pregnancy test, Ungerleider was told she was not a carrier.

Seven months later, a pediatric ophthalmologist noticed a cherry-red spot on Evan's retina, a tell-tale sign of Tay-Sachs. By then, Ungerleider knew all the indicators. "When the doctor muttered under his breath, I said, 'Oh, my G0D, I know what this means.' "

The couple later discovered that the pre-pregnancy test had been misread.

Infants and children with Tay-Sachs gradually lose the ability to move, eat, see, swallow and breathe without assistance. Evan quickly regressed, needing more and more in-home nursing.

Parents on average spend $60,000 per year caring for children with Tay-Sachs, said Ken Bihn, president and co-founder of the Cure Tay-Sachs Foundation.

Evan had numerous seizures daily. The most effective mix of medicines only reduced their frequency. "Neurologists said it was like stepping on one ant and 100 more would come," his mother said.

A second child, Justin, was born when Evan was 2 1/2. The Ungerleiders tried to make family life as normal as possible.

"We spoke to a wonderful doctor who told us, 'Just cherish the time. It won't be a full lifetime, but make a lifetime happen with what you have,' " said Ungerleider, who has three symptom-free children. "We took that advice to heart."

Evan died at home in New Jersey a few months before the Horaks discovered their sick lambs in Texas.

The Horaks quickly turned to veterinary pathologists at Texas A&M University to find out what killed their lambs. They determined it was a genetic disorder but could not pinpoint it and began consulting other experts.

After tracing the lambs' ancestry to a ram named Turner 183K, the Horaks began breeding the ram's descendants for diseased sheep to help continuing research at Texas A&M. Their goal: Aid development of a carrier test for the mysterious genetic disorder so breeders could cull their flocks and protect the rare sheep.

On a tip from another researcher, Edwin Kolodny obtained diseased Jacob sheep samples from Texas A&M. Kolodny had co-founded the Tay-Sachs Gene Therapy Consortium in 2007 to consolidate research into developing a treatment for humans.

Kolodny, now retired, determined that the lambs had died from Tay-Sachs, and it was a near-match to the disease the consortium was researching in people.

Kolodny called the Horaks in 2008 with an offer to buy any carriers. The couple agreed to keep breeding for the defect.

"I have never been more touched than when I learned this could help children," Joan Horak said.

Roughly 10 years after the deaths of Evan and the lambs, Kolodny delivered an update to the New York chapter of the national Tay-Sachs association. He talked about the Horaks, their Jacob sheep and the potential for finding an effective treatment.

Shari Ungerleider, at that time a board member of the New York group, recounted the story that night to her son Justin, then 12. It inspired his bar mitzvah project. Justin started Adopt-A-Sheep in Evan's memory, raising money to help cover the cost of feeding and caring for the Horaks' research flock.

The carrier herd moved to Auburn in 2013 when the Horaks moved to Gettysburg, Pennsylvania. Four rams and 21 ewes produced 48 lambs last year for the research, with nine developing symptoms, said Ashley Randle, who manages the flock and houses breeders on her husband's family farm in Auburn.

Justin ran Adopt-A-Sheep for several years before NTSAD took over the project. "I never expected it to go nationwide," he said. "Helping families not go through what my family has gone through is all I ever wanted to do," said the freshman neuroscience major, who worked in a consortium lab last summer. "I will do everything in my power to help find a cure."

A treatment followed by a cure -- if either happens -- is way down the road.

"We haven't gotten our heads around that stage," said the NTSAD's Kahn. "It has not been tried on humans. We are still trying to get through the various challenges and steps of getting a drug to patients --- particularly gene therapy, which is new and relatively untested."

The consortium originally set a 2013 target to start clinical trials. But a setback led researchers to considerably retool the therapy. The new goal is to start trials in 2017.

The underlying technology in gene therapy is advancing at a dizzying pace, putting research on a fast track, said Martin, a professor of anatomy, physiology and pharmacology at Auburn's College of Veterinary Medicine. Money is a major hurdle to finding a treatment for Tay-Sachs in people, researchers and advocates say. The consortium's work so far has cost about $6 million, funded by the National Institutes of Health and private foundations.

Clinical trials will cost at least $2 million more. "If I win the lottery, I will write a check that same day," Sena-Esteves said. "Unfortunately, I am not that lucky."

It may take luck, said Bihn, the Cure Tay-Sachs president.

Federal budget cuts make further NIH grants more difficult to obtain, researchers said. Ideally, a biotech company would step in. But it will be a challenge to find one willing to underwrite research and development of a treatment whose commercial potential would be limited by the disease's relatively small number of patients worldwide, researchers and advocacy groups said.

That leaves grants from private groups including NTSAD and the Cure Tay-Sachs Foundation. Any delay in finding a potential treatment is frustrating, said Bihn, whose daughter died from Tay-Sachs at 14. "If we could fix just one kid, the money would come," he said.

It is one of many contrasting realities in this story. In the past 10 years, researchers say, potential for a human treatment shifted from theoretical to probable. But that is two lifetimes for an infant with Tay-Sachs.

What has been accomplished is a tale of persistence aided by modern technology. But Martin and Sena-Esteves also marvel at the backstory, how an ancient breed of sheep linked to the Jewish patriarch would have a nearly identical genetic defect to one that would be discovered some 3,000 years later in a Jewish subgroup that still carries the highest risk of developing Tay-Sachs.

"Any other sheep and you'd say, 'OK, they're sheep,' " said Sena-Esteves. "What are the chances they would be Jacob sheep? What are chances a human cure could come from a farmer's curiosity about what was wrong with his lambs? Sometimes I ask myself, 'Can it all be coincidence?' "

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