Before you read on, make sure you take a look at Pt. 1 of our interview, which goes over what PGAP3 is, Lucy’s story, and the reasons behind why Zach and Geri launched Moonshots for Unicorns. 

Moonshots for Unicorns

Moonshots for Unicorns was founded on a desire to find cures for single-gene genetic disorders – and to improve the lives of all affected. Zach and Geri explain that the name represents:

that hail-mary pass – when you have two seconds left in the game, what do you have to lose? The reality is that sometimes people do make a catch. Unicorns are these rare, magical, super-special beings and we’ve always thought of Lucy as our unicorn. So Moonshots for Unicorns highlights our attempt to develop these unique solutions for these unique kids.

Moonshots for Unicorns was also founded because funding a gene therapy can be too much for any family to take on alone. Their initial focus has been on AAV9 gene therapy, the early research for which is underway at Nationwide Children’s Hospital.

Moonshots for Unicorns: The Main Focuses

Over the last 12-18 weeks, Zach and Geri have been focusing on three main things:

• How to help Lucy today. This includes things like treating her with B6 supplements, getting her a soft helmet to help with falls, and giving her Miralax to help relieve some of her gastrointestinal symptoms. The latter, Geri says, comes from the power of diagnosis; learning how PGAP3 affected her was transformative in how they thought about her medical comorbidities and what they could do to make Lucy more comfortable.
  • Drug repurposing. Perlstein has been working with Zach and Geri to create scientific models of PGAP3 in yeast. One yeast experiment is a knockout (with no PGAP3) and the other a knock-in (putting Lucy’s abnormal PGAP3 in and seeing how the yeast works). Zach explains: 

    “We can get a catalog of about 6000 drugs and test them on the yeast in a fast and efficient way. Based on the law of probability, a few – incidentally – should improve the yeast. We hope to see a few ‘hits’ that make the yeast grow normally that could potentially be safe medications for kids.”

    If promising drugs are found in the yeast, they will be tested on PGAP3 mice and Lucy’s own cells in the lab to see if they are safe and helpful before giving them to Lucy.

• Long-term gene therapy development. This is designed to help patients who are missing a protein or enzyme that can be replaced with gene therapy. Recently, scientists have created the first-ever human PGAP3 neurons in a dish. Now researchers can check whether these neurons appear differently than normal neurons or whether it is possible to identify biomarkers. The next step, Zach explains, is developing those neurons and identifying the expression profiles. From there, they can begin the process of testing the potential gene therapy on the neurons, in animal models, and eventually in a clinical trial. The Jackson Laboratory is working to develop a mouse model of PGAP3 to assist with evaluating gene therapies.

So What’s the Plan?

In May 2022, Lucy underwent a punch biopsy to donate her skin cells. These contain fibroblasts, which scientists can transform into almost any type of cell in the body. These cells have been developed into neurons and scientists are currently working on developing other brain cell types from them.

The first phase of gene therapy research, which is fully funded, focuses on establishing and characterizing Lucy’s fibroblasts; establishing and characterizing in vitro models of neurons, astrocytes, and iNPCs; and generating four gene therapy vectors to test in mice models. Next, Phase 2 focuses on generating source plasmids for clinical manufacturing, running a small-scale safety study, and preparing IND documents for FDA submission. Phase 3 hinges on clinical trial testing and getting the doses to children in need.

In the future, Zach and Geri hope that Moonshots for Unicorns will be able to expand outside of PGAP3 and provide cures for other genetic disorders.

The Power of Diagnosis: A Final Word

Receiving a rare disease diagnosis can be both scary and relieving. On one hand, Zach and Geri are unsure of what to expect in the future. On the other, they are better able to understand their daughter. Geri says:

We watched Lucy gain and lose skills in a way that sometimes made us feel crazy. We worried about her falling behind. Once we got the diagnosis and read the literature, we became so much happier about every milestone she achieves. And with seeing those milestones, we’re also able to step up physical or occupational therapy.

Right now, Lucy loves to stand, crawl, babble, and smile. She is still a bit unstable, often falls, and is still not quite close to walking independently – but her parents describe her as incredibly resilient.

Through Moonshots for Unicorns, Geri and Zach hope to not only provide cures, but to provide comfort and support to families in need who – unlike Lucy – may not have received a diagnosis yet. Prior to their experience, Geri’s PGAP3 mutation was unknown. The family is working with Invitae to determine how many people have autosomal recessive alleles relating to PGAP3 to see if they can figure out how many people, worldwide, may have it. Zach shares:

We think there’s 700,000 people worldwide with Geri’s mutation. There are likely hundreds or thousands of people with the alleles we know who aren’t getting a diagnosis. Instead, some kids are universally diagnosed with autism or global developmental delays. We’re hoping that, once we develop a treatment and people start testing for it, the number of PGAP3 cases will significantly rise.

Head to Moonshots for Unicorns to donate or to learn more about their mission.