Two in Eight Billion

Against incredible odds, brothers born with a mutation never seen before may have found a treatment, thanks to the pro bono work of Charles River and the N1C Donated Resource Center 

Imagine waking up one day and realizing that one of the things that makes your sons unique is a genetic mutation found nowhere else in the world and with no apparent treatment. Those were the astounding odds facing Dalila when a scientific team from Singapore informed her 18 months ago that the strange and progressive onslaught of symptoms afflicting her sons had been triggered by two mutations in the spns1 gene. The gene encodes a protein that moves specialized lipid cells across membranes; when it is damaged it can lead to an accumulation of toxic substances in cells.

Devastating though the news was, it paradoxically provided much-needed clarity that helped guide Dalila toward a potential genetic solution for 17-year-old Benjamin and 8-year-old Sammy. Last year, the N=1 Collaborative, an international network of experts working together to bring individualized treatments to rare disease patients, notified Dalila that hers was the first of five applications selected to receive pro bono assistance from Charles River Laboratories through the Donated Resource Center. As part of this program, Charles River designed a series of drugs that target one of the mutations in the boys’ spns1 gene, and the drugs are now being tested by the laboratory in Singapore. 

“For me, it’s like a dream come true,” says Dalila. “After all these years, to knock on the right door and to receive the right help is fantastic. And I'm so thankful. I don't even think that I can find the words to explain how much this means to me.” 

A drug that rescues a mutation

The molecules Charles River designed belong to a class of drugs called antisense oligonucleotides (ASOs), which are pieces of custom-made DNA or RNA designed to restore functional protein in cells. ASOs are increasingly becoming a pathway of choice for people born with rare diseases, with more than a dozen approved by regulators for more common rare diseases like Duchenne muscular dystrophy, and many others customized for a single patient or handful of patients with extremely rare genetic conditions.

Roxana Redis, PhD, Associate Science Director of Advanced Modalities at Charles River, designed the ASOs for Benjamin and Sammy, which target the first exon of the gene. By interfering with the cell’s natural translation process, the drug forces it to produce a specific protein isoform that it wouldn’t normally do so under typical conditions.

The location of this mutation on spns1 was fortuitous, says Roxana. “The boys have one type of mutation on one allele [version of the gene]  inherited from the mother and a different mutation on another allele inherited from the father. Because the mother and father are healthy, we know you can have a healthy life if only 50% of your protein is produced,” said Redis. “There wasn’t anything we could do about the other mutation, but for the one at the beginning of the sequence we were able to design an oligonucleotide to force the ribosome to make a smaller functional protein that is naturally occurring in the human population.”

While it is still early days, with many unknowns and no guarantee of success, having a potential drug in hand is the first real glimmer of hope for Dalila in years. Just getting her boys diagnosed took an unusually long time. 

A multi-organ disease

Dalila said the first hint something was awry was when her eldest son Benjamin, now 17, developed prolonged jaundice after birth. Caused by high levels of bilirubin in the blood, jaundice is fairly common in new babies and usually clears up within a month. In Benjamin it persisted for months. Doctors in Sweden, where Dalila lives, found he also had elevated liver enzymes that continued to climb throughout infancy. He also had high levels of creatine in his muscles.

As he developed, Benjamin was able to sit up and walk normally compared to other boys, but his speech was delayed; his parents began to notice he had balance and coordination problems, too. “It was like he was always one step behind his peers,” said Dalila. “So, for many years, we just went to different doctors. Then we learned that there was a constant buildup of fibrosis in his liver,” she said. Benjamin also had a build-up of muscle in his left ventricle and drusen deposits in his eyes. 

Because Dalila has two healthy daughters, doctors initially thought Benjamin’s condition was triggered by a spontaneous mutation. But nine years ago, when Dalila had her youngest child, Sammy, the same painful clinical picture re-emerged. Both their doctors in Sweden, and the US National Institutes of Health’s Undiagnosed Disease Program where Benjamin was enrolled, deduced the boys had inherited the same disease, but neither had seen it before or knew what it was. It wasn’t until a research group in Singapore generated fibroblasts from the boys’ cells that at least part of the mystery got solved. The Singapore team had been studying the exact mutation on the spns1 gene in their laboratory. They just had never seen a live case before. 

Dalila said a paper describing her sons’ condition is now in development. “I believe anytime soon they will be publishing it. Once they do that, we will know, even more, and maybe hopefully, the [condition] will have a name,” she said. She also hopes that publishing a paper on this genetic disease might help find other children with the same condition.

Sharing scientific resources

Without the Donor Resource Center, it is unlikely Dalila would have been able to find a potential treatment for her sons. Investments in rare disease research, while expanding, can’t begin to cover the more than 10,000 rare diseases that have been identified, especially ones afflicting just a few. Barbara Killian, a Marketing Executive with Charles River’s Discovery Team whose passion is raising awareness of rare diseases, said the idea behind the Donor Resource Center was twofold. “The thought was that if the industry has the technologies why not at least donate a portion of it to get these services to families that are waiting, and to elevate the application of ASOs and other personalized therapies for rare diseases,” she said. “The other good thing about the N=1 Collaborative is that we are sharing data.  So not only are we bringing families in with many different rare diseases and trying to get their therapies started, or at least a personalized medicine evaluated, once we start working on those technologies the data is going to be shared in a way that will help advance technology.” 

Roxana said she was gratified to be able to help and that Charles River provided a pathway to donate her services. “I was allowed to use my volunteer hours to do the design” says Roxana. “Every year, we have a number of volunteer hours that we can use towards doing some community work, and I thought this was one of those things that fits perfectly because I can use the volunteer hours to help with the families that really need it.”

The ASO is now in the hands of the Singapore team. If all goes well, the drug will be tested in animals and then in Dalila's boys. “It has really given us something to live for, to look forward to,” she said. “It's very big. It's huge for us.”  

From Mystery to Medicine: The Science Behind a Mother’s Search
Dalila Sabaredzovic spent years searching for answers to a medical mystery affecting both her sons. What she found was more than a diagnosis—it was a global collaboration, a scientific breakthrough, and a spark of hope for families facing the rarest of diseases.
Listen to the Podcast