A Rare Disease Foundation Takes a Novel Approach
OpenTreatments, begun by the father of a sick child, uses technology to expedite gene therapies
The first few minutes of an infant’s life are precious for couples, but Sanath Ramesh and Ramya Ramaswamy knew right away something was wrong, very wrong with their son, Raghav. They expected the chubby-looking boy from those grainy ultrasound images to emerge as all babies do, howling, hungry and awe-struck at the world around them. Yet in life Raghav had practically no muscle resistance in his arms, and barely moved his body.
Almost immediately, doctors suspected an underlying neurological condition and admitted Raghav to the neonatal intensive care unit for 21 days. When the infant was discharged, he was dependent on a feeding tube and could barely lift his toys.
“We came back home hoping that everything would be fine, hoping that he would just grow into the strong and happy boy that we wanted him to be,” said Sanath. “Yeah, since then he’s been quite different.”
How different became clear on Raghav’s first birthday. The family was gathered at a park near their Bellevue, Washington apartment eager to celebrate this milestone. As Sanath was about to cut his son’s birthday cake, a geneticist called to deliver a stunning diagnosis. Using whole exome sequencing to search for all of the protein-coding genes in Raghav’s genome, the doctor told Sanath and Ramya that his lab was able to pinpoint a highly ultra-rare disease-related variant for SSMD, a mutation in the GPX4 gene, as the likely trigger for the litany of symptoms now afflicting Raghav. Only eight other children are known to have this mutation.
Sedaghatian type Spondylometaphyseal Dysplasia (SSMD) is an extremely rare progressive disorder that is congenital. Most patients die in the first days after birth due to respiratory distress, a bullet Raghav thankfully dodged.
“The GPX4 gene itself is quite small and the mutation is a homozygous point mutation that my son has,” says Sanath. “The mutation causes abnormalities in his brain. He has optic nerve and auditory nerve problems. He has some significant skeletal dysplasia. In layman's terms, he cannot eat anything by mouth. He cannot sit, stand, talk, or walk, or even hold a toy. According to the literature, kids with this condition could have cardiovascular problems, kidney problems and other chronic problems.”
A Unique Foundation
When parents learn their child has serious and life-threatening disease, particularly an incurable one, they are naturally driven to do something. Some build networks for other families to communicate and connect, others start companies to develop and accelerate a customized therapy, others lobby governments to appropriate more money for research. They raise money. Sanath and Ramya decided to pour their energies into forming an unusual foundation designed to help families in their journey to find a gene therapy for their child. In some ways it was a natural fit for Sanath, a software engineer for Amazon who makes his living creating software to simplify the lives of their customers. His rare disease foundation, OpenTreatments, is sort of aimed at doing the same thing except in this case the goal is to help families better understand the process of gene therapy drug development.
OpenTreatments is currently working with a handful of foundations that have a more advanced presence in research. These groups have money in the bank or are actively raising money for research, have a scientific advisory board and understand the origins and causes of their disease. They also are all on the path toward building a gene therapy treatment.
“Yes, this eliminates a lot of people, but at the end of the day, these are the folks that are knocking on the doors of biotechs in hoping to get treatments developed. If we can start by helping these people, eventually we can start helping a lot of others in earlier stages of this process,” says Sanath.
The assistance that OpenTreatments provides typically begins with a gap analysis and a roadmap. The roadmap gets into a software platform that the can be used to track that foundation’s progress. Clients can also consult an array of service providers, including Charles River Labs, for assistance in filling some of those gaps in the drug development roadmap.
Sanath is also in the process of creating a process structure to help patient foundations progress their project. “At the end of the day, I’ve heard a lot of people say that, ‘Oh, yeah, I would really benefit from someone telling me that this is too slow or someone telling me that I’m not on track so can I correct myself.’ ”
Expert advice on gene therapies
Sanath has found that foundations typically want to understand how viable their program would be when they take it to the US Food and Drug Administration, and what challenges to anticipate when running a clinical trial. They need to know what the trial design will look like. “Patient foundations also struggle with animal models because they are really interested in getting to a mouse model that has the highest deficiency or the highest demonstration of the disease so they can prove efficacy of the drug, said Sanath. “But a lot of the diseases affecting these families don't have strong mouse models, or even if they do, they don't know if they would be sufficient enough from a regulatory standpoint.”
This is where OpenTreatments tries to help, by connecting scientific experts with families for free. David Fischer, Executive Science Director at Charles River said when cases get to a point where “you know the gene, disease symptoms, then one of our scientists will look at the cell type, the organ where the gene is expressed, potential route of administration, and its safety implications.”
Fischer says there is clearly an enormous need for scientific assistance in the rare disease community, particularly those dealing with ultra-rare diseases. “Because there often isn’t a biotech or pharma exploring these diseases, we get quite a number of questions directly from families,” says Fischer. “We try to help them, but we don’t advertise this aspect of our work because Charles River typically works on rare disease indications for biotechs, larger foundations and pharma, so having this non-profit [Open Treatments] take on the role of a gateway provides more accessible routes for these families. ”
Aside from the time devoted to OpenTreatments start, Sanath and Ramya, who recently moved to San Francisco, continue to search for a therapy to help their son. Raghav has already been prescribed five different drugs, and Sanath is in the processing of getting a sixth one started—a repurposed drug developed initially for multiple sclerosis. “Some medications did help, but they did not provide the quality of life improvements we expect”, said Sanath.
“Some of these drugs have mechanisms of action that tie back into the gene that my son has a mutation on,” says Sanath. “Some of them connect back to the pathways or impact other parts of the cells that would potentially help relieve the pressure of the lack of this protein for my son. That's how we've been approaching the repurposing—in terms of what it could correct. We don't know, honestly.”
Because there are no biomarkers for Raghav’s condition, Sanath says the best measurements to look for are quality of life improvements. “We haven’t seen any of that yet unfortunately, a least so we can definitely say this is due to the drug. We have been using these drugs for quite a while and they don’t really show any overnight improvement.”
Through it all Raghav has developed a surprisingly patient and happy personality. He laughs and smiles all the time. And as he gets older, he is learning how to demand his parents’ attention. He is learning to express anger. He uses facial expressions as his means of communication.
“When I got my COVID vaccine, I was sitting there, holding my breath and fighting my arm,” said Sanath. “The nurse had to tell me to relax. When Raghav gets his vaccine shots, he just looks at his book and wrinkles his face for a split second, and then goes back to his book. That’s how much of a fighter he is.”