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A family’s global research journey searching for a treatment for PIGA-CDG

When Ann and Steve’s son, Emmett, was diagnosed with the rare disease PIGA-CDG, it set them on a mission to find a cure. Using their own skills and with the help of their friend Andrew, with a PhD in molecular and medical pharmacology, they have immersed themselves in a global scientific community, learning all they can to drive research.

I think all rare disease parents become experts in their own child’s condition. When you spend so much time in the hospital without specialists, you have to find out all you can yourself. It just happens, and we too, became the experts on Emmett’s condition and care.

Ann and Steve 
Ann and Steve with their family
Getting a diagnosis: the early signs and symptoms of PIGA-CDG

When Emmett was born in April 2016, he presented with medical issues from the start, remaining in the neonatal intensive care unit (NICU) for the first ten days of his life. He was given the all-clear and discharged; however, Emmett failed to meet milestones such as smiling, holding his head up and sitting. Later that year Emmett was hospitalised for a month and a half with respiratory problems and seizures. Initial epilepsy panels came back negative, so the family underwent whole exome sequencing. It was through that that Ann and Steve received Emmett’s rare diagnosis: PIGA-CDG. There were no treatment options or research into PIGA-CDG, and Emmett spent a lot of time in hospital with gastrointestinal and respiratory complications. Most children with PIGA-CDG struggle with a range of symptoms, including global developmental delays, seizures, muscle tone disorders, recurring respiratory illnesses, and more. Some end up needing feeding tubes and/or tracheostomies. And, as in Emmett’s case, many end up passing away at a very young age.

A lack of signposting and accessible information led to Ann and Steve searching for answers alone

At one point I was looking up online classes on biology and neurology and genetics, just trying to learn the basics.

Steve

When Ann and Steve received Emmett’s diagnosis, they found it difficult to find out about the disease and whether there was any research. Any information they did find was very scientific and not available in lay language. Their geneticist and neurologist pointed them to PubMed publications where there was a handful of papers that documented similar mutations and characteristics of the disease. But, there was not anything beyond that, and the rarity of Emmett’s disease meant the couple also struggled to find other families with the same diagnosis.

Searching for treatment options with an international team

Steve reached out to his friend Andrew, and with his help the family began their research journey. They started by focusing on small molecule replacement. The idea was to understand the role the PIGA gene played in the body, and what small molecule replacements might be supplemented to make up for the PIGA gene’s impaired function. The research and networking led them to a researcher in Osaka, Japan and a chemist in Germany. The lab in Japan had discovered a lot about the different genes involved in the pathway that PIGA-CDG was in and the researcher agreed to work with them. They used Emmett’s cell lines to assess whether various supplements had a noticeable impact. In Germany, the chemist worked with them to create a new molecule that was essentially the output of what the PIGA gene created. Whilst this showed great promise in vitro, when tested in mouse models, the results could not be replicated. 

​At this point, with limited funds, Ann and Steve shifted their focus to gene therapy. Through Steve’s work, they were able to make connections with companies that specialised in cell and gene therapies. “In principle, if you have a disorder that’s caused by a single mutation (monogenic) and the gene itself is within a certain size, it should be viable for gene therapy,” Steve explains.

Creating interest in ultra-rare diseases

The problem is finding somebody to help us—most of the companies I had connections with were busy with their existing pipelines—many companies weren’t interested in a disease with fewer than 100 patients.

Ann and Steve

However, their contacts did provide a consensus that, in principle, gene therapy should work for the disease. Eventually, Ann and Steve were connected with Nationwide Children’s Hospital in Ohio and a researcher at the hospital. Ann and Steve continue to work with them today, along with other researchers in Japan and Utah. (The researcher in Utah is working with them on a drug repurposing project for PIGA-CDG, in parallel with the gene therapy project.)

Preparing for the next steps to drive PIGA-CDG research towards a treatment

At present, the couple are focused on proof of concept for a gene therapy. With a successful outcome in-vitro, the next stage is to test the gene therapy vector in mice, which they hope to receive results for in the next six months. Once this testing stage is complete, the next stage will be safety and toxicity—which Ann and Steve have already begun fundraising for.

“The amount of money we need for clinical grade manufacturing and clinical trials is in the millions. It’s too difficult to raise these kind of funds on a non-profit basis, so we know we need to look at external funding and partnering”, Steve explains. “We hope that once we have proof of concept data, there will be a good level of interest from gene therapy companies.”

Building a website to raise awareness and unite families globally

Awareness is really critical, for both education and to raise the money we need for life-saving research.

Ann

When exploring ways to fundraise, Ann and Steve decided to partner with CDG CARE, the oldest CDG non-profit in the world. They felt it would be beneficial to work with an organisation that had an established structure and process, as well as network. Through CDG CARE, three grants have been awarded for PIGA-CDG research, one of them being for the current gene therapy project.

They also decided to start a website dedicated to sharing information and resources on PIGA-CDG to help other families who may be newly diagnosed. And that number seems to be increasing. When Emmett was diagnosed in 2017, there had only been 20 published cases of PIGA-CDG. A more recent research paper shows that there are now almost 100 published cases of PIGA-CDG, most likely due to increasing genetic testing.

The whole effort has been an international one, working both with researchers and families. A lot of the families that we’ve been connected with are more active outside of the US — Europe and Latin America – and we need to continue the search to find others.

Ann and Steve
Building a legacy for Emmett: finding a treatment that will benefit others

“When we started our research journey, it was to help Emmett, and the hope was to develop something in time to improve his condition”, Steve explains. Sadly, a treatment was not found in time for Emmett, who passed away February 2020 just shy of his fourth birthday from respiratory complications. But Ann and Steve continue to advocate and drive forward PIGA-CDG research in the hopes that it might help other families.

Emmett

Emmett was on this earth for such a short period of time but, because of his life, if we can make a difference in helping others find a treatment, that will mean so much to us—that’s what keeps us going.

Ann and Steve

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