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Turning the tide for rare disease

Finding a cure nobody else is looking for: why Geri and Zach shoot for the moon

Doctors, Geri and Zach Landman, have a daughter called Lucy with an ultra-rare disorder called PGAP3-CDG. Through their foundation, Moonshots for Unicorns, they hope to find a cure for the condition and bring hope to other families affected by single gene disorder

By Chelsea Wong and Geoff Case

Lucy’s diagnostic journey

When Lucy was born, she was just like her sisters—smiley, happy and playful. Geri and Zach expected her to start sitting up in her chair for food at four months old, but instead, she flopped to the side.

As a mother and paediatrician, Geri could tell something wasn’t right, so she pushed for a neurologist’s appointment. A rapid MRI looking at Lucy’s brain structure followed, and Geri and Zach were reassured everything looked fine. 

The family went back to living life as normal, until Lucy picked up a routine cold, during which she refused solid food and became incredibly fussy. She had started to sit unassisted, but she was really off balance and kept falling from side to side. Geri took Lucy to the emergency room for some basic tests. Once again, she was reassured that everything was fine. 

Geri started collecting videos of the things that were worrying her and sent them to the neurologist, who admitted Lucy for a workup. A battery of tests followed, but they brought no answers. However, the neurologist, who also happened to be a geneticist, ordered a broad panel 480-gene test to find out if there was a genetic cause. 

A month later, Geri and Zach were told that Lucy had two bad copies of the PGAP3 gene—meaning that she had an ultra-rare glycosylphosphatidylinositol (GPI) anchor disorder called PGAP3-CDG. Because of this, cellular communication proteins don’t stick well to the outside of her cells, affecting her neurons and her brain development.

Having been constantly reassured everything was fine, and with Lucy apparently making progress, the results shocked the couple to the core.

“We never expected anything to ever show up on those genetic tests because we were reassured so many times.”

The doctor had never had a patient with PGAP3-CDG before, but she had read that the condition can lead to severe developmental delays, so Lucy would be severely intellectually disabled. She would not be able to perform activities of daily living (ADLs), such as bathing and eating, would not have speech, may or may not be able to walk and would be likely to develop severe seizures. 

The condition’s rarity meant there were no treatments, and the doctor couldn’t find anyone researching treatments for PGAP3 anywhere. 

Geri and Zach raced through the stages of grief. First came denial. They stayed up through the night reading every paper, every piece of information they could possibly find. Each of Lucy’s slight abnormalities wouldn’t be considered meaningful individually, but together they clearly pointed to PGAP3. By the next morning, Geri and Zach knew Lucy’s diagnosis was the right one.

Once further testing confirmed the diagnosis, Geri and Zach told their older girls and they spent time grieving as a family.

Moonshots for Unicorns

There came a point where we looked at each other and said we can’t spend the rest of our lives crying about this. So, let’s do something about it. There’s no one in the world better situated than we are as physicians in the Bay area among biotech hubs, so let’s get on it.”

Geri and Zach began emailing experts researching therapies potentially applicable to Lucy’s condition, such as gene therapy, ASO technology (antisense therapy) and drug repurposing.

Geri got in touch with Dr Kathrin Meyer, who was on the team that worked on Zolgensma, a life-saving gene therapy medicine for spinal muscular atrophy (SMA). Dr Meyer explained that gene therapy could potentially help with PGAP3, especially while Lucy was still young, her symptoms mild, and her brain plastic. If Lucy had gene therapy early enough, it could improve her condition. Hope was born.

On paper, gene therapy seemed like the perfect fit for Lucy. There was only one issue—to develop a gene therapy and get Lucy infused in a trial would cost $2–3m (US dollars). Geri and Zach immediately knew they needed help—a GoFundMe page was never going to help them achieve their goal. Geri and Zach needed to do this through a foundation, which is when Moonshots for Unicorns was born. Through setting up the foundation, Geri and Zach made it their mission that no parent would ever have to go through their experience with PGAP3-CDG, or, ultimately, any single gene disorder.

“What we’ve learned from the scientists about gene therapy is—like building the first Ford Model T—things are really expensive early on, and the technology is clunky. But as it matures, things get streamlined, faster and easier…

We hope that Moonshots can help spur the time in the not-too-distant future when you can have a gene therapy can be developed in months—without millions of dollars for each one, not treating every one as brand new.”

Gene therapy for Lucy was Geri and Zach’s biggest push, but knowing that it could take two years or more, it was not their only consideration. They got into contact with Ethan Pearlstein, founder and CEO of Perlara. Ethan works primarily with rare disease families on drug repurposing, especially for congenital disorders of glycosylation (CDG)—Lucy’s condition is a subcategory of this family of rare genetic metabolic disorders.

Ethan had found a repurposed drug for a child called Maggie, who has a similar condition to Lucy, and this really improved her walking and speaking. After months of therapy with a repurposed drug—a Japanese nerve pain medication—Maggie was walking, talking and colouring inside the lines. It was pretty transformative, and for Geri and Zach it was inspiring. 

However, Geri and Zach’s main focus is developing a gene therapy for their daughter and getting it approved by the FDA. To this end, the couple are talking with as many experts in gene therapy as they can. “We’re all about perfecting the science of gene therapy and advancing that field. The more we tweak it, the more effective it becomes,” Geri says.

Lucy’s skin cells that have been turned into neurons

Shooting for the stars

Geri and Zach feel that every child with a rare disease is a unicorn—they’re magical and unique. Their ambition is that the innovative Moonshots for Unicorns project will give Lucy and other children with rare single-gene disorders a shot at a brighter future. But time is of the essence.

“The reality for rare disease patients, especially ultra-rare, is that nobody is coming to the rescue. There’s no knight on horseback showing up… Which is why Moonshots for Unicorns is so important.”

Credits

Family photos by Kree Photography


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