Hope where there was none

“Enjoy your time with him,” said the genetic counselor. Linda and Tommy Pham’s son, Raiden, had just been diagnosed with UBA5 disorder, an ultra-rare, life-threatening disease with no available treatments, and these words signified a devastating take on his prognosis. 

Looking back on this guidance and where their family is now in their journey—driving the urgent development of a gene therapy that could potentially save Raiden’s life—Linda said: “It’s hard to enjoy each moment with Raiden. We don’t have time for that.”  

Raiden was born healthy during the winter of 2020, and met typical milestones until age three months, when Linda and Tommy noticed a decline in his development. He lacked head control, contorted his body into unusual positions, was forcefully vomiting after feedings and seemed to be in pain.  

As Raiden’s health deteriorated, an intensive medical journey began, involving hospitalizations, gastric-feeding tube insertions, multiple rounds of genetic testing, and a desperate search for answers—all amid a global pandemic. It would be more than a year before a definitive diagnosis arrived in August of 2021. 

For the last two years, the Phams have been on a race against time, working to raise money that will support research efforts at UMass Chan Medical School in the hopes that a breakthrough treatment for this devastating disease can be found before it’s too late. The family, from Beaverton, Oregon, is targeting gene therapy for its potential to effectively treat UBA5 as well as other rare diseases. 

UBA5 disorder is caused by a genetic mutation in the UBA5 gene that results in protein malfunction, leading to this life-threatening neurological disease. Symptoms typically involve movement impairment, seizures, muscle tone and brain abnormalities, intellectual disability, respiratory complications and failure to thrive. There are only 40 known cases in the world. 

Linda and Tommy spent about a month grieving Raiden’s diagnosis—what they describe as “the darkest of the darkest time.” 

Then, they turned to science, which offered a ray of hope where there had been none. 

‘We need science now’

Leaning into his science background, Tommy scoured research papers in search of biomedical advancements that might help Raiden. Linda and Tommy eventually connected with the team at UMass Chan’s Translational Institute for Molecular Therapeutics to explore the development of a targeted gene therapy—perhaps the best chance to give Raiden and other children with UBA5 disorder hope for a better life. 

Gene therapy is an emerging medical treatment in which a functional copy of a defective gene is delivered to patients with the aim of correcting the underlying cause of the disease. The functional copy of the gene is delivered through viral vectors, which are viruses engineered to safely transport the genes with great precision. While it may still ring of science fiction, gene therapy has the potential to dramatically transform the way we treat a wide range of diseases, from rare disorders to cancer.  

To fund the UBA5 research, Linda and Tommy launched the Raiden Science Foundation. Their goal is to raise at least $3.2 million to support the research all the way to delivery of a therapy that can be tested on Raiden. “We need science now,” said Tommy. 

“It is now feasible to design therapies for individual children, or for children with entire groups of genetic mutations that might be treatable by gene therapy,” said Terence R. Flotte, MD, the Celia and Isaac Haidak Professor, executive deputy chancellor, provost and dean of the T.H. Chan School of Medicine.

“It’s a hopeful time but also a time where we’re somewhat on the precipice because the clock is ticking, and the child may have a condition that continues to progress as we’re working on the research. That makes it all the more crucial that we accelerate translating knowledge about what the gene is into some form of therapy,” he said.

The Translational Institute for Molecular Therapeutics was launched in 2022 to address just this type of need. Families who have a child with a rare disease have few options because not much may be known about the genetic mutations associated with the disease; and because it is rare, funding opportunities for developing treatments is limited.

“The Institute came about with the recognition that we have fantastic basic research, but then we don’t have an outlet for it, and investigators have to do a lot of work themselves to make it go from the bench discovery to the clinic,” said Miguel S. Sena-Esteves, PhD, associate professor of neurology and director of the Translational Institute. “We have established a pipeline that moves the program seamlessly from the discovery all the way to the clinical trials and having regulatory support.”

Dr. Sena-Esteves said that this streamlined translational approach will be less costly than nonintegrated research and therapeutic development models, which will ultimately lower the entry barrier into clinical trials.

Research on UBA5 supported by the Raiden Science Foundation is led by Toloo Taghian, PhD, instructor in Dr. Heather Gray-Edwards’s lab in the Department of Radiology and Horae Gene Therapy Center.   

Currently, Dr. Taghian has identified the top two viral vector constructs for UBA5 expression in-vivo, which show great promise in successfully delivering UBA5 gene therapy to the targeted cells. Dr. Taghian and her team will soon be evaluating their efficacy in correcting the protein malfunction and treating the underlying cause of this disease, and shortly thereafter will initiate toxicology studies to study their safety.   

“Working with Raiden Science Foundation to develop a gene therapy for UBA5 has been an impactful journey,” said Dr. Taghian. “The dedication of the Pham family in supporting UBA5 research allows the UMASS Chan team to work towards unpacking the basic science underlying this ultra-rare disease in parallel to our gene therapy development program. Tommy and Linda’s appreciation and feedback motivates us to push forward this fast-paced program, face the unknown and keep our hopes high when we encounter obstacles.”

Raiden’s legacy

As UMass Chan pushes the science forward, Linda and Tommy are “pushing to fight for a better tomorrow.”

They say there are times when they want to give up, when the weight of managing Raiden’s intensive caregiving needs while also raising their older daughter, Jordyn, running a household and holding down full-time jobs—plus trying to raise millions of dollars for UBA5 research—is just too overwhelming. 

Indeed, driving the Raiden Science Foundation is itself a herculean task that requires enormous time and effort, as well as publicly sharing their story. Culturally, and as private people, this is not something that comes naturally to Linda or Tommy. “We are not social media savvy,” said Linda. “We worry constantly about whether or not we can raise the money.”  

Despite the challenges, the Phams and the Raiden Science Foundation have raised $1 million for UBA5 research, a remarkable accomplishment. Their creative, grassroots fundraising efforts include fighting game charity events under the banner Fight4Rare—Tommy is a lifelong gamer and also happens to be the gaming partnerships lead at Nike—thereby tapping a unique global community. 

Raiden’s role in an experimental treatment also weighs heavily on the Phams. “It’s scary that he’ll be the one testing the treatment,” said Linda. “But you look into Raiden’s eyes, and you can’t give up. And once we have a treatment, it won’t just be for Raiden.” 

Indeed, the Phams believe that their efforts are enabling a platform for the future of personalized medicine that will help treat countless rare diseases in the future.  “Instead of celebrating Raiden’s developmental milestones, we’re celebrating scientific milestones,” said Tommy. 

It’s fitting that Raiden’s namesake is the God of Thunder in Japanese mythology (who also features in “Mortal Kombat,” the popular video games franchise). Because of him, biomedical researchers are building the knowledge required to counter a deadly disease, and eventually, others like it. The work will never be in vain. 

“It’s Raiden’s legacy,” said Tommy.