Moonshots for Unicorns

My daughter Lucy absolutely loves the water – whether it’s a warm bath or a refreshing pool, that girl will stay in and “SPLASH SPLASH SPLASH” with her sisters and dad forever. On a recent family vacation, she got a little cold, but I knew something was up because she wasn’t interested in the pool and seemed especially tired, fussy, and floppy. And when we came home, things got worse. Our normal routine on school days was to lay her next to her sleeping 7-year old sister – her cute babbles were the only way to get her night owl big sis to wake up in a good mood before school. However, over the next few days, she wasn’t babbling much at all and her older sister complained, “I can’t get Goose to smile at all this morning.” We soon met with the neurologists at Stanford’s Lucille Packard Children’s Hospital, who were also concerned. They conducted an extensive workup including a brain MRI, EEG (for seizures), spinal taps (for infections and neurotransmitter problems), and EMG / nerve conduction studies, all of which were reassuring and couldn’t explain why she was seemingly so off her baseline. After about a week, however, the symptoms mostly went away and she returned to her babbling and smiley self, albeit a bit less strong than before. To be thorough, though, broad genetic testing was sent off.

One month later, we received the text no parent ever wants to get: “Lucy’s genetic tests are back and I’m concerned. Let’s meet in an hour.” No surprise, I spent that hour in the bathtub splashing with Lucy, trying to distract us all in her happy place. Then came the shocking news that Lucy has two bad copies of her PGAP3 gene, one of the many genes involved in sticking important molecules to cells and in cell communication. She has one tiny amino acid difference in one tiny protein – yet, it’s an essential one. And when she’s sick, even with a common cold, her cells work and communicate even less effectively. Her diagnosis is extremely rare, with only a handful of other patients known worldwide. We weren’t the only ones shocked; her pediatric neurologist also never suspected, given Lucy's overall mild symptoms, that she would be delivering such a devastating diagnosis. Most kids with PGAP3-CDG are markedly disabled and develop very severe symptoms in early childhood years. At 11 months, Lucy sits, babbles, plays, and is working toward her first steps. We were told that there is currently no cure and no treatment, and that she will likely suffer from low muscle tone and ataxia, have moderate to severe intellectual disability, develop autistic features, never develop expressive speech, and may develop intractable seizures. We looked through tears at our smiling, curious baby and defiantly didn’t believe it.

Unfortunately, the genetic diagnosis is true. Equally unfortunately, given that so few people have this genetic disorder, there are no trials anywhere in the world for PGAP3 and there is no active research on developing a therapy for children with PGAP3. However, we are still defiant, and there is good reason to believe there is a lot of hope for Lucy. One of her copies of PGAP3 is a new variant, which may be slightly milder than cases described previously. Few children with this disorder have ever been diagnosed so young or had such a mild initial presentation. Most importantly, our neurogeneticist at Stanford has connected us with Dr. Ethan Perlstein, a Harvard trained PhD scientist, and Perlara, his biotechnology company based in the Bay Area, that exclusively works directly with families whose children have genetic disorders similar to Lucy's (“congenital disorders of glycosylation”). Since 2014, Dr. Perlstein’s research teams have worked to identify potential cures for these single gene mutations. For instance, Perlara worked with the family of Maggie, a child who has a genetic condition very similar to Lucy's. In 2019, the team developed the scientific models of her gene first with yeast, then more advanced models, to test existing medications that might be re-purposed to make her faulty protein more functional. A rarely used, but safe, Japanese nerve pain medication was found to boost the necessary protein by 400%, which was sufficient to reverse many aspects of the disease. The drug was given to Maggie, and the results were astounding. Two others with the disease also had similar results. The medicine is now FDA approved for a phase 3 trial at Mayo Clinic for dozens of children with her disorder.

Using these exact same models already created, the researchers can relatively simply switch Maggie’s gene with Lucy’s gene to identify an effective therapy and potentially a cure. Lucy is young, and as my grandfather would say, there is light behind those eyes – she is curious, loving, chatty, and has not yet developed any of the more serious features of this syndrome. She is truly an N-of-1, with a novel variant and a novel set of life circumstances. No child in the world with her condition has had the opportunity to have an effective treatment so early in life, which means that the sky is the limit to what we can do for her.

Unfortunately, because there are simply not enough kids known to have Lucy’s genetic disorder, no pharma company, government, or investor is interested in funding this research – it has to be us. In order to accomplish this, the research team needs about one year of full-time to work to build Lucy’s gene into yeast, worm, and fly models, test nearly 6,000 compounds to determine which boost her protein’s expression or function, and then ensure that compound does the same thing in Lucy’s own fibroblast (immune) cells, using the same playbook as the identification of Maggie’s drug above.

As I write this, Lucy is playing on her mat with her two big sisters, cracking up as she accidently squirts her sister with one of her bath toys still filled with water. And yet I remember those few days she made less eye contact, fell over easily, and stopped babbling just because she had a little cold, and I feel the floor drop out from under me - the thought of losing Lucy, this little person she has already become, is inconceivable. With your help, we can start the work nearly immediately and realistically find and begin a treatment by her second birthday, before any of the more severe symptoms are expected to develop. Lucy will be the N-of-1, but the work done for her treatment will hopefully lead to treatments for the dozens of children suffering from this condition around the world. Please help us fund this research and give Lucy the gifts of speech, walking, and a life without seizures.