In honor of Rare Disease Day on February 28th, I spoke with Manchester resident, Caitlin Eppes, to learn about her mission to find a treatment or even a cure for her young daughter, Avery. We spoke about how Caitlin has learned to harness the power of research to help drive progress, how two Averys came together to create a community, and her hopes for the future of The Avery Project, the research project she founded:
Welcome, Caitlin. Why don’t we start with learning about Avery’s story, and how you found yourself in the world of rare diseases.
My daughter Avery was born in 2017 after a healthy pregnancy and normal newborn screening. At birth, Avery had some red spots on her forehead, eyelid, and the back of her head and our pediatrician referred us to a dermatologist. That started us on our diagnosis journey, which lasted for two years. After extensive genetic testing, we received the news that Avery has a randomly occurring, single-letter change (a point mutation) in a gene affecting a key metabolic pathway known as sphingolipid metabolism, which plays a key role in cellular signaling, brain development, immune response, and are very important components of our cell membranes.
We were relieved to have a diagnosis, however, the geneticist told us that the variant Avery had was categorized as a “variant of uncertain significance”; it wasn’t linked to any known disease, and there was limited research on the gene. Avery is the first person in the world reported to have this variant. [What I have since learned is that] in the US, a rare disease is defined as a disease that affects fewer than 200,000 people; an ultra-rare disease is defined as affecting fewer than 2,000 – yet, here we were as just one.
I’ve never felt more alone or scared as I did at that moment.
What were the first steps you took when you found out Avery’s disease did not fit into any pre-existing medical conditions? Can you share how you navigated finding treatment when the disease didn’t even have a name?
This question takes me back to such an intense period of time for our family – how to proceed when there was little to no information available about Avery’s condition. Her geneticist advised us to check PubMed for new articles related to Avery’s gene or her variant, and if nothing surfaced, to come back in five years, and perhaps there would be new insights or treatments available. After two years of searching for a diagnosis, though we finally had one, it brought no answers, in fact, it arguably raised more questions.
Rare diseases account for 35 percent of deaths that take place in the first year of life and 30 percent of children who have a rare disease will pass away before their fifth birthday. So, while we’d made it past year one, no one knew if Avery would make it to year five.
I started reading stories about other rare disease families and how they started foundations, how they partnered with pharma to repurpose drugs, and how they raised money for the development of new treatments and therapies. But we still didn’t know what we needed to solve for. We needed research; someone to figure out what is the change in Avery’s gene doing to her body? We know it affects sphingolipid metabolism – but how? Why does that matter? And how can we treat it?
I found a neurologist at Mass General Hospital, Dr. Florian Eichler, whose lab focuses on single-gene mutations affecting lipid metabolism and I met with him to discover more about how research is started, funded, published, and leads to meaningful treatment.
Can you tell me about The Avery Project, how it got started, and what the goals are?
Dr. Eichler became interested in Avery’s case and used data from her genetic reports to create yeast models to get an idea of what the gene was doing. Preliminary results helped him understand that Avery’s variant was causing a biochemical change that was the exact opposite of what took place in diseases that he previously researched and treated.
Dr. Eichler and I discussed how to accelerate research, receive a federal grant, and develop a treatment. Given that Avery was the only person with this variant, it would be difficult to obtain a research grant quickly because so much more data was required to develop an appropriate hypothesis and run sufficient tests. We were in a race against time since the course of this disease is unknown. Our discussions shifted to privately funding the initial phases of research, and in November 2019 we launched The Avery Project, a research fund within MGH under the direction of Dr. Eichler for his team and collaborators to conduct the experiments, secure model organisms, and explore treatments related to Avery’s genetic variant.
The team was making great progress, our genetically altered mice were in development in China, then the pandemic started. Labs closed down, members of the team were assigned to ER shifts, priorities changed. While we waited for things to normalize, we received a call from Dr. Eichler, excitedly sharing with us that they had found another person with the same variant and that their family had been given our contact information and I would have to wait for them to call me. I couldn’t believe it – there were two people with this variant! We had a community! I kept thinking, my gosh I hope they call.
How were you able to locate the one other known person who shares Avery’s condition?
Upon receiving Avery’s diagnosis, her genetic variant was entered into a global database known as Gene Matcher, which can be used to find others who have an interest in the same gene. Our team was notified in June of 2020 that there was a match, not only on the gene but the exact same variant. This meant that we didn’t have to rely just on the mice and the other organism models – that there was another person out there who had the same diagnosis as Avery. The family called us one month later, and we learned that they were from North Carolina and had been searching for nine years for a diagnosis for their daughter and were finally accepted into the Undiagnosed Disease Network. As they told me their daughter’s name, I knew why Dr. Eichler was so excited in his phone call to us – their daughter’s name is also Avery. There we were – two East Coast families, both with young daughters who shared a name, a variant, and big brothers who loved them, and families on a quest to contribute to science, identify treatments and help others avoid the stress and ambiguity that we had experienced.
Can you share a bit about what The Avery Project accomplished and what your hopes are for the future?
I’m so amazed by what the teams have accomplished over the past two years. They have created model organisms in yeast, mice, and flies. They created cell lines from skin and blood samples from both girls, these allow them to confirm certain observations in other models. Just over one year after the initial funding, the team received two R21 grants totaling $150,000 – a process that typically takes several years.
Most recently, the team submitted a paper for peer review to The American Journal of Human Genetics, and they are applying for a large grant from the National Institutes of Health (NIH). My goal for The Avery Project is to discover a treatment or hopefully, a cure. Only 5 percent of rare diseases have treatments, so if we make progress, it will benefit our daughters and the entire rare disease community.
Charlotte Lawrence is a junior at Manchester Essex Regional High School. As the school district’s student health ambassador, she seeks to raise awareness about issues that impact the health of our students and community.
