Over the past 18 months, the use of the latest biotech technologies to develop and produce mRNA vaccines to fight COVID-19 has driven investment funding in healthcare and biotech to all-time highs. Those technologies include gene-editing tools such as CRISPR/Cas9 and are leading to more scientific discoveries that could usher in a new era of therapeutics.

“We are entering a space now where technology and medical breakthroughs are intersecting,” says William Blair research analyst Raju Prasad, Ph.D., who covers the biotech sector. “We’re seeing a generational shift in this decade to genomic medicines, like the mRNA vaccines—but for all kinds of diseases. It’s moving extremely fast.”

Raju Prasad
Raju Prasad, Ph.D., William Blair research analyst

What grabbed the attention of scientists, biotech companies, and investors in gene editing this summer were the results of a Phase 1 gene-editing trial conducted by biotech Intellia Therapeutics.

Presented at the Peripheral Nerve Society’s annual meeting in June and concurrently published in the New England Journal of Medicine, it was the first clinical report of gene editing conducted inside the human body (in vivo) that was safe and effective. After a single dose, Intellia’s in vivo CRISPR/Cas9 treatment knocked out the gene in patients suffering from an inherited liver disease, known as transthyretin amyloidosis (or ATTR).

“It’s a significant milestone for the field as it demonstrated the initial feasibility and short-term safety of clinical, in vivo gene editing,” Prasad says.

Up until this discovery, successful gene editing was conducted “ex vivo,” where cells are taken out of the body, changed, and put back in.

Additionally, the delivery vehicle to transport the CRISPR/Cas9 gene-editing system into the cell to treat the rare liver disease was the same delivery platform used in mRNA COVID-19 vaccines: a lipid nanoparticle, or LNP.

These tiny balls of fat protect delicate mRNA, strands of genetic material, as they cross the cell membrane and deliver the technology prompting cells to defend against infections and diseases.

Paving the Way

“It’s taken over a decade to find something viable we can use for delivering functional CRISPR/Cas9 in the clinic,” says William Blair biotech analyst Myles Minter, Ph.D. “It turns out if you use a lipid nanoparticle, you can fit the entirety of the CRISPR/Cas9 complex, deliver it to cells within the liver in patients, edit the target gene and potentially have therapeutic benefit. It just so happens the lipid nanoparticle used in Intellia’s initial candidate looks pretty similar to what everyone gets in the COVID-19 mRNA vaccines.

“We can take the safety learnings from literally hundreds of millions of vaccinated people, change the lipid formulations and get them to target specific cells for more tailored treatments of all kinds of disease.”

Take oncology therapies like chemotherapy as an example. It’s used to kill tumors but can cause systematic toxicities causing hair loss, skin discoloration, loss of appetite, and other disorders.

“Instead, what if we put these therapeutics in a lipid nanoparticle directed only to the tumor so it doesn’t kill out your hair, doesn’t make you sick—just hits the tumor for treatment,” says Minter. “Now expand the payload to include therapies for both devastating rare diseases like cystic fibrosis or more prevalent disorders like cardiovascular disease. Using the lipid nanoparticle as a delivery system to improve safety and efficacy of approved therapies and those in development, that’s where the promise is beyond the vaccines.”

Myles Minter
Myles Minter, Ph.D., William Blair research analyst

CRISPR 2.0 Pioneers

The CRISPR/Cas9 system, guided by mRNA, acts as scissors to cut a targeted DNA within the cell so the DNA repairs itself, explains Prasad. But with next-generation CRISPR technology, the DNA machinery can come in and correct a specified gene—not by cutting the DNA but by acting like a pencil and erasing one letter on one strand of DNA to cure illnesses. The method, known as base editing, is a more refined version of CRISPR/Cas9 editing.

“It’s an elegant system that takes into account the potential implications of genetic damage,” Prasad says.

There are several pioneers in the CRISPR 2.0 space, all with a vision to provide life-long cures for a wide range of diseases. Among those are Beam Therapeutics with its in vivo delivery programs using lipid nanoparticle technology targeting liver diseases. In February, it acquired Guide Therapeutics—a company spun out of Georgia Tech developing DNA-barcoded libraries of lipid nanoparticle technology for drug delivery to broaden the reach of gene editing. 

Another trailblazer is Massachusetts-based Verve Therapeutics. It has licensed Beam’s base editing technology to develop genetic medicines for cardiovascular diseases. So far, Verve has been successful in knocking out two genes that raise cholesterol levels. While Verve is a year or so away from initiating its first human study of its lead candidate, VERVE-101, it continues to make research advances. Its goal is to disrupt the chronic-care model to treat heart patients with a one-time treatment, thus changing the lives of tens of millions of people.

Prasad says one of the most likely genomic medicines that could be first available for patients is CRISPR Therapeutics-Vertex’s CTX001 product to cure sickle cell disease and another for a rare blood disorder called thalassemia. Both were developed ex vivo. The companies are targeting as early as 2024 for potential FDA approval.

What’s Ahead for LNPs

Other considerations for the biotech field are the manufacturing capacity for LNPs and managing the supply line of raw materials required, analysts say. Previously, lipid nanoparticles had largely been created in academic labs, mixed by microfluidic machines to produce small batch quantities. But the pandemic vaccine response has proven lipid nanoparticles can be produced at massive scale and rapidly, despite some supply chain constraints.

Matt Larew
Matt Larew, William Blair research analyst

Ultimately, the application of lipid nanoparticles could become a $40 billion to $60 billion therapeutic market in the next five to seven years, far beyond an estimated $4 billion to $8 billion annually for the LNP-mRNA vaccine market (excluding the initial few years of COVID-19 vaccine bulk contract selling), according to a recent William Blair research report released in June.

“In the last 18 months we’ve gone from learning what COVID was and characterizing its DNA sequence to using mRNAs as a construct to build those vaccines to now producing billions of doses of mRNA-based vaccines which are delivered via LNPs,” says William Blair analyst Matt Larew, who covers companies providing life science tools to researchers.

“At an industry level, LNP manufacturing is still in the early days of scaling up. Most companies we talk to believe this is a flag in the ground moment for the use of LNPs as delivery platforms,” Larew adds.

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