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Producing the newest medicines - and potentially cures: gene and cell therapies

Posted December 31, 2020 11:26 a.m. EST

At Novartis Gene Therapies, the company's goal is to develop and commercialize gene therapies for patients and families affected by rare and life-threatening neurological genetic diseases. Already, its initial gene therapy for spinal muscular atrophy has been approved in the U.S., Japan, the European Union, Israel, Brazil and Canada. (Photo Courtesy of Novartis)

This article was written for our sponsor, the North Carolina Biotechnology Center.

Gene and cell therapies are paving the way to breakthrough treatments and potential cures for serious illnesses and diseases, from spinal muscular atrophy to Pompe Disease.

Pioneers scientists in this field call North Carolina home.

Research by Jude Samulski, Ph.D.,at the University of North Carolina at Chapel Hill used adeno-associated virus to deliver gene therapies. His findings created Bamboo Therapeutics, now part of Pfizer, and AskBio, acquired by Bayer. Charles Gersbach, Ph.D., leads Duke University's Center for Advanced Genomic Technologies, whose CRISPR research underpins a half-dozen startups. And North Carolina State University's Rodolphe Barrangou, Ph.D., uses a different CRISPR enzyme to edit genes. This technique underpins the work of Locus Biosciences.

With this foundation, North Carolina's strengths in biological manufacturing naturally created a cluster of gene and cell therapy manufacturing, including Novartis Gene Therapies, Audentes, an Astellas company, and more.

"Gene therapy alleviates the underlying cause of genetic diseases and acquired diseases. It aims to treat diseases by replacing, inactivating or introducing genes into cells— either inside the body, or in vivo, or outside of the body, or ex vivo," said Jimmy Weirich, vice president and site head at Novartis Gene Therapies, a global healthcare company with a major manufacturing facility in Durham. "Each cell and gene therapy is designed based on detailed information about the roots of a patient's disease. Rather than treating symptoms, gene therapy works by repairing or enhancing cells at the genetic level."

According to Weirich, the aim of gene therapy is to halt a disease in its tracks or reverse its progress, as opposed to simply alleviating symptoms. The treatment is often only administered once.

At Novartis Gene Therapies, the company's goal is to develop and commercialize gene therapies for patients and families affected by rare and life-threatening neurological genetic diseases. Already, its initial gene therapy for spinal muscular atrophy has been approved in the U.S., Japan, the European Union, Israel, Brazil and Canada.

That treatment, the company's flagship gene therapy in neuroscience, Zolgensma, was approved in May 2019 in the U.S. to treat children less than two years old with SMA. Given as a one-time infusion, the treatment helps halt irreversible motor neuron loss and disease progression.

In developing this treatment, Novartis Gene Therapies hopes to change the lives of those afflicted with SMA.

"The healthcare industry in general – and gene therapy in particular – is incredibly fast-paced and changing every day. It's exciting and requires people who want to think differently about challenges and the solutions needed to be successful," said Weirich. "At the end of the day, though, it is all about our patients. To know that our hard work means we can change the life of one single patient and his or her family is an incredible feeling. There aren't many industries or jobs like that."

At Audentes, the company has a similar focus, utilizing gene therapies to target life-threatening and often rare diseases. Based in California with a location currently under construction in Sanford, Audentes develops gene therapies to treat conditions like X-Linked myotubular myopathy, Pompe disease, Duchenne muscular dystrophy and myotonic dystrophy.

The company is currently implementing its plans to construct a $109 million, state-of-the-art gene therapy manufacturing facility that employs 200. Growing its footprint in the Triangle brings further opportunities to the area, complementing the potential of gene therapies in general.

"One of the real benefits that we have when it comes to using DNA as the therapeutic agent is that it's incredibly flexible. It serves as the basic instructions that allow you to create antibodies, or enzymatic proteins, or RNA molecules with your gene therapy. You can take this very basic building block and design it in a way that allows it to interact and change just about any aspect of cellular biology and redirect and refocus it in a way that we think is beneficial to the patient," said Mathew Pletcher, Ph.D., senior vice president of research at Audentes.

"What gene therapy does is it takes a benign virus and gets rid of the viral elements that allow the virus to replicate and make multiple copies of itself. We get rid of that and then put in the DNA we wish to deliver into cells. So we hijack something that exists in nature and now use it as the vehicle to deliver therapeutic genes back into the patient's cells."

In the case of a condition like Duchenne muscular dystrophy, Audentes is able to use gene therapy to implement interventions like exon skipping — a type of RNA splicing that redirects cells to skip over mutationa. Through these techniques, scientists can restore normal gene function by removing the mutation.

Locus Biosciences develops antibacterial products using CRISPR-enhanced bacteriophages. By targeting certain bacteria, this Morrisville biotech company employs precision therapy to treat bacterial diseases, disrupting the microbiomes of patients as little as possible.

"Historically, bacteriophages haven't been effective enough to fight serious infections because bacteria and bacteriophage co-evolved over billions of years into a sort of predator-prey relationship — so they're in this sort of ecological balance. We addressed that by enhancing the killing capability of the bacteriophage using CRISPR," said Joseph Nixon, senior vice president of business development at Locus. "We add CRISPR-Cas3 — instead of snipping the target DNA like a pair of scissors, it shreds it or chews it up like a Pac-Man. What we do is put the CRISPR-Cas3 constructs into the bacteriophage and thereby create a dual mechanism of action between the bacteriophage itself, killing some of the target bacterial cells and then CRISPR-Cas3 killing the rest."

In targeting treatment in such a way, Locus is able to make products that are significantly more effective than other bacteriophage products. The products it develops are used to target bacterial infections and microbiome diseases, including conditions like inflammatory bowel disease and colorectal cancer.

Audentes, Novartis Gene Therapies and Locus are helping to create gene and cell therapies that could change the lives of millions of people across the world and address diseases in ways that weren't previously possible. In addition to the medicines and treatments the companies provide, other companies are using similar methods to treat conditions like congenital blindness, cancer, diabetes, metabolic disorders and more.

"Audentes really is one of the pioneers charting this new course and an innovative approach that we think could really transform the entire landscape of medicine — how we deliver it and the impact that it can make," said Pletcher. "Ultimately, we're at the beginning of a really exciting transformation in medicine that is going to make a real difference in people's lives. By having a nucleus of companies like ours, growth in the area can become an avalanche, where we all continue to build on top of each other."

Added Nixon, "The Triangle has a much lower cost than other leading areas, like Boston and San Francisco. Those lower costs, especially for companies like Locus, where we're funded by investor dollars, enable us to achieve more for the same amount of money. And of course, the programs with the NCBiotech Center are critical in helping to grow and sustain the life science industry in the state."

As that avalanche of opportunity continues to gain momentum, companies like these need a qualified workforce. According to Weirich, the ideal candidate for the industry should have the proper training and education, but also curiosity and a passion for helping others.

"There is a wide range of jobs, and, more importantly, career options, available within this industry. No matter the role of the job, it is fundamental for all of our employees to know that the work they do on a daily basis has a direct impact on our ability to produce life-saving therapies for our patients, and in the case of Zolgensma, our employees are literally saving the lives of newborn babies," said Weirich. "Most importantly, we are looking for people who feel as passionate as we do about the mission to make a difference in the lives of individuals and families faced with the challenge of rare diseases."

Photo Courtesy of Novartis

This article was written for our sponsor, the North Carolina Biotechnology Center.

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