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by Sandra Bretting

published in 2010

A recent $2.5 million gift to the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital has paved the way for noted Italian researcher Andrea Ballabio, M.D., to serve as visiting scientist at the institute for a year. Ballabio and his team conduct research into neurodegenerative disorders and lysosomal storage disorders, such as Batten disease.

The gift comes from Cherie and James C. Flores, who donated $2 million to the effort, and from the Beyond Batten Disease Foundation, which contributed $500,000. The foundation was established by Charlotte and Craig Benson, whose daughter, Christiane, was diagnosed with juvenile Batten disease in 2008.

Batten disease is a rare genetic disorder that attacks the nervous system. It was first documented nearly one hundred years ago, but research has been limited until now. There is no treatment and no cure. The earliest signs are subtle and often do not occur until a child is about 5 years old.

“It is heartbreaking to think that this disease will one day rob Christiane of her ability to see and walk and use her mind. And, eventually, it will take her from us, unless we act now,” Benson said.

“We have to believe that there’s an answer, and we are confident that there is hope for the future in terms of developing treatments for Batten disease,” he continued. “Texas Children’s Hospital is uniquely positioned to make progress against genetic disorders like Batten disease through facilitating collaborative research and recruiting world-renowned scientists like Dr. Ballabio and his associates.”

Ballabio has served on the molecular and human genetics faculty of Baylor College of Medicine. Currently, he is the scientific director of the Telethon Institute of Genetics and Medicine in Naples, Italy. He and his team recently discovered the gene that controls the body’s ability to degrade and recycle toxic molecules. The build-up of these molecules is the cause of numerous genetic disorders, including Batten disease, along with other neurodegenerative disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases.

“We have identified a ‘master’ gene that acts as a genetic switch,” Ballabio said. “By enhancing the function of this master gene, we can increase the clearance capacity of the cell and its ability to degrade toxic proteins. We believe this knowledge will help us develop better treatments and, ultimately, find a way to prevent these diseases.”

Phase one of Ballabio’s research at Texas Children’s began in July and is focused on the development of animal models for Batten disease and other disorders. Phase II, beginning next summer under the leadership of Ballabio’s research associate, Marco Sardiello, Ph.D., will investigate which drugs are able to promote activation of the master gene.

https://waystogive.texaschildrens.org/page.aspx?pid=1765

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by Kevin Davies in Bio-IT World

published March 16, 2010

‘The day we got Christiane’s diagnosis was a horrible, obviously very painful day. Disbelief. Despair. Sorrow. Agony. Fear. And unbearable pain. It forever changed our path.” – Charlotte Benson

Christiane Benson started to lose her vision two years ago, at just five years of age. She is legally blind, suffering primarily from a loss of visual acuity. “We’d never heard of Batten disease, but it completely changes your life forever,” says her father Craig Benson, CEO of Rules Based Medicine, a biomarker testing laboratory and diagnostic company in Austin, Texas.

As Benson and his wife Charlotte researched their daughter’s incurable neurodegenerative disease, they found many family foundations dedicated to raising money for similarly rare genetic disorders. “With a disease that affects so few people, it’s hard to get attention when there’s so many other good causes,” says Benson. He wanted to make his own foundation—the Beyond Batten Disease Foundation (BBDF)—relevant for an audience outside Batten disease. “Fortunately, I work with people who are a lot smarter than me,” he says. Among them were his business partner, a serially successful scientific entrepreneur named Mark Chandler, who was founder/chairman of Luminex, and his chief medical officer, Mike Spain.

“We thought, treatment and cures are great, but how do we prevent a disease like this? We were familiar with the Tay Sachs model in the Ashkenazi Jewish population that took pretty aggressive carrier screening and family counseling to virtually eliminate that disease in that population over about 15 years,” recalls Benson. “It appeared the only hindrance to taking that exact same proven strategy to a much broader perspective was technology and cost.”

Chandler happened to serve on the board of directors of the National Center for Genome Resources (NCGR) in Santa Fe, New Mexico. Benson called NCGR director Stephen Kingsmore, who has a background in orphan diseases. Kingsmore supported Benson’s ideas about a universal carrier screening strategy using next-generation sequencing to offer, as Benson says, “not just a handful of diseases like CF or Tay Sachs or Pompe’s or adrenoleukodystrophy, but actually try to take every medically devastating autosomal recessive or X-linked condition and multiplex it and put it on a sequencing platform… It’s perhaps the first and initially the best utilization of the sequencing application. You get meaningful, actionable information out of it.

“They decided to be quite audacious about it,” says NCGR’s Callum Bell, formerly of Genzyme. “Rather than just look at a single disease, study the long tail of diseases that are individually very rare, but if you add them up they become quite common. A few percent of live births have some kind of genetically related problem.”

Time and Money

Benson says his goal is “to put 500 diseases we’ve selected, what we consider the most medically devastating diseases, onto a single panel. Our hope is to offer that test for less than $500.”

The current Beyond Batten list is actually 437 disorders. “In OMIM [Online Mendelian Inheritance in Man], there are about 1000 recessive diseases with a known gene. Our panel is aiming to address about 450 of those,” says Bell, who is leading the Beyond Batten project.

The criteria were recessive disorders that caused childhood fatality or extreme childhood disease. Some disease foundations worked with Benson to have their own gene(s) of interest included in the test. “We didn’t want any controversy that these were traits or not life threatening,” says Kingsmore. “We didn’t want to get into any stigma with doing carrier testing. [It had to be] morally unequivocal.” One issue is that there are still some diseases where patent holders are unwilling to share their exclusive rights, a plight Kingsmore calls “tragic, because these tests are not economically viable unless on a panel.”

The NCGR will use a next-generation sequencing platform to sequence the coding regions of all 437 disease genes (see “Technology Target”). The plan is to set up a new CLIA-compliant entity to perform the test. Kingsmore anticipates a limited launch later this year that won’t yet be a billable carrier screening test.

Benson is searching for a permanent location for the DNA analysis lab, with the choice narrowed down to four (unnamed) sites. In addition to target enrichment, compute facilities and sequencing, the partners need economic development resources to raise money to get the program off the ground.

As for when it would be offered, Benson says: “Ultimately we’d like it to become standard-of-care for a young woman at the ob/gyn.” Another likely market will be in vitro fertilization clinics, where Benson says families are already undergoing an extensive out-of-pocket procedure. He sees the Beyond Batten test as providing more information.

“It’s intended to prevent the disease,” says Bell. “It will be for couples considering pregnancy… We’re hoping it’s adopted in same way as Tay Sachs testing. Or for girls at their first ob/gyn appointment, when they get a vaccination for HPV—that would be an optimal point to have them tested. They could later make informed family planning choices based on the test results.”

Benson and Kingsmore were hoping to launch the test this May, but various issues may push that out a little.

Eradicate and Cure

The launch of a test that could encourage some to seek abortions for affected fetuses could provoke controversy, but Benson doesn’t see it that way. “My personal faith would make me concerned about that anyway,” he says. “We were not oblivious to it. Our intention for this test and the market we plan to sell into is not for someone who is 2-3 months pregnant. We’re planning to offer this testing very early, before anyone’s even thinking about a family. We think it will provide useful information for families to make decisions because there are so many choices. IVF, adoption, there are alternatives families can choose that will not lead them down that path.” Benson quotes a saying: “It’s always good to stay on the side of the angels.” That way, he says, “you can always sleep well at night.”

“Our drive is to get the cost of this down to a level that is going to be affordable without insurance,” says Benson. BBDF will get some proceeds from test sales. “We view this test and its commercialization as the means of sustainability and a permanent funding source for our treatment and cure efforts… This is not really a commercial venture,” he concludes. “This is, for us, a legacy.”

Technology Target

The NCGR will sequence the coding regions of a total of 437 selected disease genes—about 2 megabases in all. While the Illumina platform remains the NCGR benchmark, Kingsmore says the Life Technologies SOLiD system is improving, and NCGR is also one of the early-access partners for Pacific Biosciences.

Kingsmore’s original assumption was that he would screen the disease genes using a custom DNA chip, similar to those in use in clinical labs for copy number variant detection. But issues of allelic heterogeneity and the error-filled cataloguing of variants prompted him to reconsider. Taking a longer view, needing a platform that could adapt to the discovery of new mutations or genes, the choice was either redesigning the chip every six months or taking the sequencing route. “I do believe sequencing will become cheaper than chips eventually,” says Kingsmore.

Bell and colleagues have been evaluating four enrichment technologies, including Agilent, febit, and RainDance. The favorites are currently Agilent and RainDance. “Agilent is very cost effective, but there are concerns that there are some targets we can’t design for. RainDance works very nicely, but cost is an issue,” says Kingsmore.

The NCGR team is also facing unexpected challenges in validating variations and improving software. Some of the interpretation challenges Kingsmore’s group has encountered means his team needs to validate its assays to a much higher degree than he’d envisioned just six months ago. “There isn’t a gold standard database of reference material, which surprised me,” says Kingsmore. He’s finding both deleterious mutations that cause devastating childhood diseases that the literature has mis-annotated, as well as variants called deleterious mutations that are sometimes just common SNPs. “It means we’re going to have to fold into this a whole level of discovery effort I hadn’t anticipated. We want something clinically useful and actionable.”

“Everyone’s going to be a carrier for about five disease mutations,” adds Bell. “Plus, how do you deal with those for which you haven’t got a confirmed phenotype—so called Variants of Unknown Significance (VUS)? If you find a nonsense mutation or a frameshift VUS, you may think there’s an obligation to do some kind of reporting around that. A weak link will be the physician that orders the test. I don’t know that the average doctor is equipped to counsel patients based on that number of genes. If you start introducing probability of disease based on an algorithmic approach to VUSs, it gets even more difficult.”

One priority at NCGR is to upgrade the Grindstone Laboratory Information Management System (LIMS) to handle different security levels, since it will be handling clinical data and needs to be CLIA compatible. It also needs to be able to handle multiplexing. Then there’s the Alpheus variant detection pipeline (see, “Jumping on Next-Gen Sequence Data Analysis,” Bio•IT World, July 2009), which Kingsmore says is “designed to do on-the-fly query of datasets. For a diagnostic or carrier screening, we want to lock that down, giving a standard well annotated report. We’ve got to do a lot of code hardening there as well.”

http://www.bio-itworld.com/BioIT_Article.aspx?id=97662&terms=+legacy++beyond+batten+disease

A Study Started Half a World Away May be the First Step Toward a Cure

By Sandra Bretting in Shine, a magazine of Texas Children’s Hospital

Normally, when doctors deliver a diagnosis, their next words focus on a treatment or cure. But, what do you do when there is no cure and your child is the patient?

That scenario became real for the Herndon family of The Woodlands in June. During a visit to Texas Children’s Genetics Center, they learned their 6-year-old son is not suffering from a common eye ailment, like they had originally thought, but from a rare genetic disorder called Batten disease. That diagnosis sent their lives into a tailspin.

A Typical Texas Boy

As a toddler, Will loved nothing more than to play with his toy cars for hours on end. Although he didn’t learn to speak until he was 3, his parents weren’t too concerned. In every other way, he was a healthy, normal kindergarten student.

Until last fall, when his teacher noticed Will had begun to hold his schoolbook only inches from his face in order to read the words. She told the boy’s mother, Missy, that perhaps he needed glasses. Around the same time, Missy overheard Will ask his younger brother, who was 3 at the time, a seemingly innocent question.

“What color is this crayon?” Will asked his sibling. These events began a journey through multiple eye examinations and a growing fear that something was seriously wrong with their son.

“One day I told Will to be ‘patient,’ and he asked me what I meant,” Missy recalled. “Now, Will has heard me use that word a thousand times. I could tell there were gaps in his knowledge; whole blocks of information were missing.”

After taking Will for myriad eye examinations, the Herndons ended up in the office of Richard Alan Lewis, M.D., a genetic retinal specialist at Baylor College of Medicine. It was Lewis who suspected an underlying diagnosis and recommended the Herndons bring Will to Texas Children’s Genetics Center for testing.

“It was the week Will turned 6,” Missy said. “I’ll never forget that. Dr. Lewis thought it could be one of two genetic diseases. He didn’t want me to write them down because he didn’t want me to look them up and be upset.”

“Usually I’ll diagnose about one child a year with the disease,” Lewis said. “Ironically, I’ve seen four cases alone in the last two years. The interesting thing is that the infantile strains affect babies neurologically first, while the juvenile form, such as Will’s, presents as a fairly rapid deterioration of vision first.”

Battling a Deadly Disease

Batten disease is a genetic disorder that affects the body’s nervous system. Substances called lipopigments—fats and proteins—build up in the body’s tissues and these children’s cells aren’t able to break them down or recycle them.

There are three major variants: infantile, late infantile and juvenile. Will has the juvenile form, known professionally as juvenile neuronal ceroid liopofuscinosis (JNCL).

“When the results came back as Batten, we immediately said, ‘Okay, how do we fight this?’” Wayne, Will’s father, said. “And the answer was … you don’t. There’s no cure and limited research going on right now.”

Unwilling to accept a death sentence for his child, Wayne spent countless hours each night on the Internet, finding out everything he could about the disease. Fate—or divine intervention as the couple believes—brought the Herndons together with another Texas couple who were given a diagnosis of Batten disease by Lewis.

Charlotte and Craig Benson of Austin had already formed an organization called the Beyond Batten Disease Foundation that seeks to promote research into this little-known illness. The Benson’s 7-year-old daughter, Christiane, was diagnosed with Batten disease in 2008.

The Bensons donated $500,000 through their foundation to Texas Children’s Hospital. Coupled with a $2 million donation from close friends Cherie and James Flores, the gifts were used to bring Andrea Ballabio, M.D., and a colleague from Italy to America to conduct research into neurodegenerative diseases like Batten.

A Dedicated Scientist on the Hunt

Half a world away, Ballabio had already isolated the gene that controls cells’ ability to degrade and recycle toxic molecules. As scientific director for the Telethon Institute of Genetics and Medicine in Italy, Ballabio published his findings in the July 24, 2009, issue of Science magazine.

“We discovered a novel biological mechanism by which cells degrade and recycle toxic molecules,” Ballabio said. “We also found a way to enhance this mechanism to improve cellular clearance. We hope we can use this discovery to treat neurodegenerative diseases, such as Batten, which are caused by the accumulation of toxic molecules in neuronal cells.”

Along with his colleague—Marco Sardiello, Ph.D.—Ballabio will spend a year as a visiting scientist at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital. He’s also a visiting professor in the department of molecular and human genetics at Baylor College of Medicine.

The neurological research institute, which is currently under construction in the Texas Medical Center, will open next year and aims to be the preeminent research facility for pediatric neurological disorders in the country, if not the world. The goal is to give scientists, like Ballabio and Sardiello, the tools and proximity to other scientists to make the most of their research.

“It is a wonderful gift to have Dr. Ballabio working with our team,” said Huda Zoghbi, M.D., director of the Jan and Dan Duncan Neurological Research Institute. “He’s a distinguished scientist whose research epitomizes the mission of this institute.”

The Rest of the Story

Throughout the coming year, Ballabio and his team will research ways to enhance the function of master genes that regulate the efficiency of how cells clear toxic molecules.

“We are working very hard towards the application of our discovery for the cure of Batten disease, as well as other neurodegenerative diseases,” Ballabio said. “We will need time, but we hope to be successful in this difficult task.”

“We could throw ourselves into self-pity, or we could work to help find a cure,” Missy said. Recently, she joined the Blue Bird Circle, which is a group of volunteers who work with the hospital’s pediatric neurology clinic. “At some point in time every disease was without a cure. Now, it feels like it’s all coming together. I believe in my heart that these children are going to make it into adulthood.”

https://waystogive.texaschildrens.org/page.aspx?pid=1222

In honor of Rare Disease Day on February 28th

The following retailers are donating a portion of their proceeds to the Beyond Batten Disease Foundation

Austin
1379 Kids • 2727 Exposition Blvd. • 2/27
Austin Pilates Barn  • 1600 Northwood Road • 2/23 & 2/26
Bella Mi • 1601 W. 38th Street • 2/27
Bettysport • 916 W. 12th Street • 2/27
Feather Your Nest • 3500 Jefferson St. • 2/27
Hayden Avery • 1515 W. 35th Street • 2/26 & 2/27
Lee’s Meat Market • 1601 W. 38th Street • 2/26 & 2/27
Teo’s • 1206 W. 38th Street • 2/27 & 2/28

Houston:
A Bientot •3268 Westheimer Road • 2/27
River Oaks Bookstore • 3270 Westheimer Road • 2/27
Thompson Hanson Home and Garden Shop • 3600 West Alabama • 2/27 & 2/28
Tiny Boxwood’s Café • 3614 West Alabama • 2/27 & 2/28