Nasha Fitter didn’t have time. There had to be a better, faster way, she thought — not just for her daughter, who recently turned 7, but for other people with rare diseases.

Fitter tapped her tech and entrepreneurial background to create a nonprofit, the FOXG1 Research Foundation, to try to find a cure for the 100 or so patients known to have the condition at the time. The foundation worked on a natural history study, which in ultra-rare diseases can serve as a placebo arm in a clinical trial. The foundation also creates cell lines, conducts drug screens and oversees gene therapy pilots.

“It’s insane, as parents, that we’re building mouse models and cell lines,” Fitter said. “It’s insane to me that this is what we have to do.”

In a world of little hope — where parents of children with rare genetic diseases are told there currently is little or nothing that will make their kids well and often no existing effort to discover something that will — moms and dads become the most improbable of drug hunters. Within days of a diagnosis, often despite no background in the life sciences, parents latch on to experts and start reading scientific journal articles. They learn about genetics and drug development, and they explore wonky concepts like yeast and animal models and drug-testing assays.

With no guarantees of success, those parents embark on odysseys that have tripped up Ph.D.s and MDs and seasoned drug- development executives.

In essence, they make their own hope.

Chan Zuckerberg Initiative assistance

When added together, rare diseases are anything but rare. In all, 350 million of the 8 billion people globally — more than 4% of the population — have one of the 10,000 known diseases that fit the U.S. definition of “rare,” fewer than 200,000 patients.

Only 5% of those diseases have Food and Drug Administration- approved therapies.

“I always say, ‘Yes, SLC13A5 is rare, but it’s not rare in my house,’” said Kim Nye, whose oldest daughter Tessa and son Colton have mutated copies of the SLC13A5 gene that cause a type of epilepsy. “I hope we can figure out how to make all these things scalable.”

All but a handful of drug companies, such as San Rafael’s BioMarin Pharmaceutical Inc. and Ultragenyx Pharmaceutical Inc. of Novato, have shied away from rare disease drug development. For many companies, the risk, time and money it takes to develop a drug — $1 billion over 10-plus years of work, by industry estimates, to take a single drug from lab bench to patient bedside — is more efficiently spent on a treatment for hundreds of thousands or millions of patients than for a handful.

Parents and other loved ones of rare-disease patients often try to fill the void.

“When a disease is so rare, the chance that any given academic is going to come across enough patients to do a natural history study is virtually zero,” said Tania Simoncelli, the vice president of science in society at the Chan Zuckerberg Initiative. “The only way to study it is to build a patient community. Who’s going to do that? Not some investigator trying to get tenure.

“The patient community has to do that work. They shouldn’t have to, but they have to.”

The mission of the Chan Zuckerberg Initiative — a 7-year-old effort backed by pediatrician Priscilla Chan and her husband Mark Zuckerberg, the co-founder of Facebook and CEO of Meta Platforms Inc. — is to support science and technology to prevent or cure all diseases by the end of the 21st century.

Simoncelli joined CZI five years ago following time in the White House Office of Science and Technology in the Obama Administration, the Food and Drug Administration and the ACLU, where she was an adviser to the organization’s efforts to stop genes from being patented by companies. Her goal at CZI is no less ambitious: help patient organizations build networks that leverage knowledge to make rare-disease therapy development more efficient and effective.

CZI, based in Redwood City, created the “Rare As One” project initially to fund 10 pilot patient groups. Instead, the organization received more than 300 applications, and CZI in 2019 funded 30 three-year, $600,000 grants to help grassroots patient organizations build infrastructure, including paid staff, scientific advisory boards, websites and other community tools.

One of those groups was the Nye family’s TESS Research Foundation in Menlo Park.

The Rare as One network two years ago added a second cohort of 20 organizations.

“Patients have real expertise to bring to the table,” Simoncelli said. “They have the motivation and the insights to generate hypotheses. We see this over and over again, and yet it’s not really recognized.”

There are other, similarly audacious efforts to speed up the search for rare disease therapies.

Ultragenyx bootcamp

As vice president of business development at Ultragenyx in 2017, Dr. Yael Weiss organized a bootcamp at the company’s Novato campus for patients and parents looking to build new therapies. Those sessions, including an upcoming one in April, attract 20-25 participants.

In all, the bootcamp has had 110 attendees representing 85 advocacy groups.

The bootcamp aims to familiarize patients and parents with the drug-development pathway, jargon and options available to them. It also offers an opportunity to hear from experts in the rare- disease space and helps create a “mini peer group,” Weiss said.

“Times are changing and these amazing parents aren’t waiting for industry to pick up their programs,” Weiss said. “They are just doing it.”

Weiss also is founder and CEO of Mahzi Therapeutics Inc., launched two years ago with early funding from Ultragenyx and others, to mentor and support patient groups that fund early research, then in-license programs to continue drug development.

“There is so much activity in this space, and the Bay Area is a hub for some amazing parents and a great rare community, each with heartbreaking and heroic stories,” Weiss said.

Yet parents and patients continue to face sizable roadblocks, including money, time and know-how for navigating the complexities of early-stage drug research and development.

Natural history studies, for example, often rely on far-away academic centers that are challenging to reach when traveling with a young child with a rare disease. On her way to Amara’s third visit to a site three hours away, for example, Fitter’s daughter had a seizure and vomited in the car.

Fitter turned back for home.

“It’s just a ridiculous model. Health care is a very slow-moving industry,” said Fitter, who founded the tech startup Schoolie and was a director at Microsoft Corp. “There’s so much regulation. It’s always slow to change. There’s a lot of nervousness.”

Fitter landed a $482,000, four-year grant from CZI and worked with Ciitizen Corp., a Palo Alto digital health records startup that had focused on cancer. They created a natural history study that included Nye’s TESS Research Foundation and four other groups, using machine learning to scrape records and give uniformity for a picture of those neurological conditions.

“Gathering records is a big hurdle,” Nye said. “Not all hospitals were even using electronic medical records. I had a binder of printouts.”

Fitter joined Ciitizen in October 2018 as vice president or rare and neurological conditions. The company was bought last year by San Francisco-based genetic testing company Invitae Corp.

Patients, researchers and nonprofits can receive its data for free; drug companies pay for access.

“Using technology to gather information in homes, that is my passion. How can we eliminate these unnecessary complications that we are creating for these patients?” Fitter said. “Rare diseases are where we can experiment with new technology.”

‘This is what I am now’

Rare disease research and development is not a career Kim Nye saw herself in when she and her husband were in graduate school near London and Tessa was born with what would turn out to be SLC13A5 epilepsy. Nye, studying law, literature and history in Greek and Latin, was 23 years old.

Now she is a parent of two children with a rare disease — Tessa now is 19 and Colton is 9 — along with being a patient advocate and an expert in all things SLC13A5.The TESS Research Foundation, founded in 2015, supports research and helped take a potential gene replacement therapy to the cusp of a first-in-human clinical trial.

“This is what I am now,” Nye said. “I don’t have the degrees behind it and I don’t have the same type of education, but I have learned from mentors who I think are the best of the best. It’s really been a graduate-school education of sorts, just nontraditional.

“I know who I am, and it’s a role that’s needed. It’s just not a role that has a name.”

Ron Leuty

Senior Reporter - San Francisco Business Times

https://www.bizjournals.com/sanfrancisco/news/2023/03/03/rare-disease-cures.html?s=print 4/7

3/3/23, 8:41 PM

FOXG1 Research Foundation, TESS Research Foundation seek rare disease cures - San Francisco Business Times