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Precision Cell Programming in the Quest to Cure Rare Diseases

Health & Medicine
Emerging Technologies
by
Peter Bickerton, PhD
|
October 24, 2023

It all began with Rose.

Four years ago, Rodney Bowling Jr. was still Director of Molecular Genetics at XBiotech in Austin, Texas, when he received an unexpected message on LinkedIn.

It was from a worried father, Casey McPherson, desperate for help.

His daughter had been diagnosed with a rare disease. Doctors didn’t know what it was. Could Rodney, pictured with a daughter of his own and with the perfect credentials, answer some of his questions?

Kieferpix (Canva)

A phone call led to lunch, which became dinner.

“We sat there and quickly became friends and started to work out what it would take to cure Rose,” says Rodney as we chat over Google Meets.

Rare But Not Uncommon

In the US, a rare disease is defined as one affecting fewer than 200,000 people. Well known examples include cystic fibrosis and sickle cell anemia.

While each individual condition may be rare, together, they’re absolutely not.

Around 7000 rare conditions have been identified, affecting 25–30 million Americans and as many as 475 million people worldwide.

Only around 5% of those people have any sort of treatment available.

That leaves hundreds of millions of people facing debilitating and deteriorating conditions without a clear diagnosis, limited access to information, and often no options for treatment.

It’s worrying, isolating, and heartbreaking.

30% of kids born with rare conditions never see their fifth birthday.

Personalized Medicine

Yet 80% of rare diseases are genetic, which offers tantalizing hope.

Today, we have the ability to read the DNA of not just one but hundreds of human genomes in a matter of days, even hours. We can identify the genetic mutations causing rare diseases.

Thanks to decades of advances in biology and biotechnology, we can work out precisely what is going wrong in the biochemistry of a patient’s cells.

In the lab, we can grow highly specific body tissues cultured from patients' stem cells to test therapies to target a cure.

With gene editing, we can aim to correct mutations in genes. We can also use small, synthetic pieces of RNA to dim or silence aberrant genes.

When Timothy Yu’s lab at Boston Children’s Hospital showed the latter could be done, the possibility of finding a treatment for any rare genetic condition through tailored and personalized medicine drew closer.

But for pharmaceutical companies, there is no profit to be made. And for most parents with kids suffering from rare genetic conditions, it’s almost impossible to know where to turn.

For many, including Rose, it’s also a race against time.

That’s why Everlum Bio, founded by Casey McPherson, Rodney Bowling Jr., and CEO Rick Barkley, is not waiting around.

To Cure a Rose

Rose, who is seven, has a lone mutation in a gene called HNRNPH2, or H2 for short. H2 is involved in processing messenger RNA—the go-between from DNA to protein—in the cell’s genetic control center, the nucleus.

Sciencephoto (Canva)

The mutation means hundreds of messenger RNAs are not correctly processed, which leads to a number of neurological symptoms that appear to be degenerative.

“Rosie had a few words, such as Mom and Dad and Food. But she’s lost all of those,” explains Rodney. “She’s also losing her walking gait. The fear is that she’ll begin to lose other things as well.”

The quicker a treatment can be found, the greater the chances it’ll work.

It turns out that the H2 gene’s highly similar relative, H1, is active before birth before it gets shut down and H2 takes over.

Everlum’s plan is to find a synthetic RNA—known as an antisense oligonucleotide (ASO)—that can block H2, allowing H1 to resume healthy functions and correct what has been going wrong.

Enter Bit.bio

All good on paper, but cells are complicated.

Rose’s faulty H2, found on the X chromosome, isn’t expressed in all her cells. In the blood, healthy cells take over.

Most problems seem to be restricted to cells in the brain, such as neurons.

This poses difficulties for Everlum. Although they can extract some of Rose’s stem cells and grow them up to make models to test ASOs, they often either lack the problem H2 mutation or do not differentiate correctly into neurons (an issue Rodney points out could well have something to do with the nature of the disease).

Other model cell systems (fibroblasts, for instance) don’t fit the bill. You can't model a neurological disease with a skin cell.

In a race against time, armed with a potential 22,000 ASOs, Everlum needs to find the best ones. Fast.

It just so happens that bit.bio, a synthetic biology company based in Cambridge, UK, which reprograms cells for human health, supplies the very neurons Everlum needs.

GABAergic neurons, to be precise, which express H2 very highly.

Bit.bio’s “Foundational” Cells

ioGABAergic Neurons™ (bit.bio)

Mark Kotter, founder and CEO of bit.bio, says the company’s opti-ox (optimized inducible overexpression) cell reprogramming technology “is pretty foundational.”

Going back to first principles, he explains that the issue is that we don't have good models for most diseases. Rose’s is a case in point. It's very difficult to get human cells that actually suffer from the condition that you want to treat.

We’ve historically relied on animal models, which results in a very high failure rate of drugs.

Human stem cells have been researched for a quarter of a century, but advances here have been limited. Techniques such as directed differentiation, which uses chemical cues to guide cells toward a certain fate, are not precise enough to get pure cultures.

“The big problem is that stem cells are so difficult to control,” Mark explains. “You never know how many cells you’ll get. You don't know the mix of cells you’ll get. If you want to develop drugs, you need precision.”

The difference with opti-ox, says Mark, is that it makes this process deterministic.  

First, transcription factors—proteins that regulate genes—are identified that are responsible for guiding a cell to a specific fate, say a neuron.

Human pluripotent stem cells, which can become any other cell type, are then engineered to express these transcription factors. opti-ox targets safe harbor sites—regions of DNA where introduced genes will be activated, time after time, without disrupting the function of the cell.

The process is efficient, consistent, and very quick. bit.bio’s ioGABAergic Neurons, provided frozen, demonstrate structural neuronal networks within 10 days, with over 99% purity

As bit.bio’s Malathi Raman, PhD, Product Manager explains in a webinar she presented alongside Rodney, that the screening of different batches shows extremely high consistency of gene expression. 

“Every time you get a batch, it's the same,” says Mark. “That allows you to get scientific results and to move forward with your development process with confidence.”

De-risking Drug Discovery

“bit.bio bent over backward to help us,” says Rodney. “We used their cell lines as a final screen for our ASOs, narrowing the pool down to a total of seven. They helped come up with what is now in a mouse.”

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That final screen took just three weeks.

Armed with seven good candidates, Everlum’s task now is to go through safety testing in line with the FDA.

It’s an expensive process that will cost almost $2 million, which is being raised by Rose’s father, Casey, through his To Cure A Rose Foundation.

That’s why proceeding with confidence is so important, says Rodney. Before you get to a mouse, a rat, and eventually a monkey model, “you need to de-risk as much as you can to make experiments as fast and inexpensive as possible.”

For Mark, this reduction in failure rate is what opti-ox aims to provide.

“If you double the chances, you halve the costs. I think you’d be much more effective, starting with this paradigm, than just doubling the chance,” which is something companies like Everlum, working with these cells at the bleeding edge, will bear out.

To Help as Many Children as Possible

In just a year since its foundation, Everlum now has nine customers ranging from one year to 44 years old. Each of them has a different rare disease.

“We are hoping that, with Rosie's treatment and subsequent investments into Everlum, we can expand and help more kids,” says Rodney. “It is our goal to help as many children as possible.”

But Rodney concedes that money is always an issue.

The more work that Everlum does, as well as organizations such as the N=1 Collaborative, which is dedicated to sharing knowledge and data and increasing democratization of access to cells thanks to companies like bit.bio, the quicker and cheaper it’ll hopefully be to find treatments for rare genetic conditions.

And eventually, with advances in gene editing technologies such as those of David Liu’s lab, which can switch individual letters of DNA at a time, a cure.

For now, however, the major burden of costs remains with families. Will personalized medicine ever become widely available?

“I think it has to,” says Rodney. “One in 10 live births carry a rare disease. The cost to parents, the cost to society, can't be ignored.

“My concern is that siloing of data and fighting over IP could stymie the research. But I'm encouraged by the open hands and open hearts of the people that I get to work with on a daily basis.”

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