By 2027, the global gene therapy market is estimated to reach a staggering value of $6.6B. With the number of successfully approved gene therapies increasing, the sector has moved from hype to hope. At the heart of gene therapy lie viral vectors, which are used to transport a gene into a target cell. Here we explore the current bottleneck in viral vector production, why viral vectors still outshine non-viral vector solutions, and what we can expect in the future.

The gene therapy field is gaining momentum. Investments are pouring in. The FDA is estimating that by 2025 it will approve between 10 and 20 cell and gene therapy products every year. This shows that a treatment, which started out as a hype, is now a real hope, says Ratish Krishnan, Associate Director of Cell and Gene Therapy Bioprocessing at MilliporeSigma*.

Today, a number of treatments have been approved, such as Spark Therapeutics LUXTURNA, the first FDA approved in vivo gene therapy, or Novartis Zolgensma, which gained US approval in 2019 and European approval in March 2020.

One of the key ingredients of gene therapies is the viral vector, which is used to transfer a gene of interest into a target cell. The most commonly used vector is that of the adeno-associated virus (AAV). But the manufacturing of viral vectors and scaling up their production remain difficult.

In upstream development, one challenge is the way viral vectors are produced. In a process called transient transfection, plasmids carrying the DNA of interest are introduced into host cells that will produce the viral vectors.

But host cells are commonly grown in adherent cell cultures, which are usually harder to reproduce at a large scale. So to scale-up and achieve high titers of virus particles, researchers are working on growing cells in suspension using large bioreactors instead.

We are facing several challenges at the moment and that is what keeps us on our toes, Krishnan adds. In upstream development, there is a desire to move towards suspension. Most processes use transient transfection methods using plasmids and the transfection step at a production scale of 500L or 2000L is extremely challenging.

In downstream development, researchers are studying the purity of capsids. The capsid is the protective shell of the virus enclosing the gene of interest. Related to this is an important discussion on the purity of viral vectors.

When you produce vectors, you will generally have a population of empty capsids, which is the viral AAV assembly without the genetic material inside, or partially-full capsids with only part of the DNA inside, Krishnan explains. We have to better understand the role of empty capsids inside the body. Are they needed as immune decoys or are they strictly considered impurities? In theory, you only need the ones with all the DNA inside, the full capsids.

But researchers have yet to discover the correct percentage of full capsids in a drug substance or product, Krishnan says. We dont have the answer yet. Typically, the strategy leans towards the enrichment of a percentage of full capsids as high as possible, while taking into account the data from clinical trials.

Questions about purity are difficult to answer because there is little or no regulatory guidance. For instance, compared to monoclonal antibodies (mAbs) for which the regulatory environment is well understood, the regulatory landscape for gene therapies remains largely unclear.

Through decades of research, mAb production also works through well-established and standardized platforms, whereas viral vectors are still in their infancy and cannot be produced using platform technologies yet although much is being done in this field and they are catching up fast.

Because of their longstanding history, we already have a lot of knowledge and research about mAbs, Krishnan explains. Lets say I want to start a biotech company or a CDMO that develops mAbs. I can rely on existing templates and get up and running much quicker than if I were developing viral vectors.

AAVs come in many different serotypes distinguishable strains which impact platform development. The scale-up is also challenging since the indications can be strikingly contrasting. For example, ocular indications need smaller viral drug substances compared to a muscular indication.

Manufacturing mAbs is better understood than manufacturing viral vectors. Viruses are a whole lot bigger and can be more complex than antibodies. While antibodies usually have a size around 10 nm, AAVs measure around 20nm and Lentiviruses around 100nm in size. Not only are antibodies produced at a larger scale than viral vectors, but their scalability is also more predictable due to the established platform technologies.

Despite these challenges, the increase in popularity, investments flooding in, and the promise of essential cures have led to a bottleneck in viral vector production for gene therapies. But many companies working in the gene therapy field are small or emerging biotechs that do not have the necessary resources and expertise in-house to tackle the challenges of viral vector production.

Lacking the facilities to do it themselves, small and emerging biotechs therefore turn to experienced contract development and manufacturing organizations (CDMOs), such as Merck BioReliance, to produce their gene therapies.

There are only a handful of CDMOs that have the capability and expertise to take on the complexities of gene therapy projects, Krishnan says. But there is currently a bottleneck in manufacturing slots. Manufacturing facilities can only work 24 hours a day, and if you are a small company and a CDMO has other clients waiting in line before you to have their therapies manufactured, you have no other option but to wait.

The problem with waiting, of course, is that the biotech runs the risk of falling behind its competition. Krishnan emphasizes, time is of the essence in gene therapy. There is no silver medal for developing a therapy for the same indication.

The key, says Krishnan, lies in much planning and close engagement with the CDMO partner. Biotechs should do an analysis of what they can perform in-house versus what they have to outsource early on. Engaging a CDMO is the route you want to take.

With decades of experience, Merck can support its biotech sponsors all the way to the clinic. We are big on the concept of integrated solutions, Krishnan explains. From clone to clinic to commercialization, Merck has the expertise, knowledge network, product, and services to help guide any customer to the finish line. We have the CDMO expertise with BioReliance, with testing services, gene therapy expertise, and regulatory support.

To circumvent the manufacturing bottleneck for viral vectors, some biotechs are looking at non-viral vector solutions for gene therapies. While traditional gene therapies use a viral vector, like AAV, to transfer a gene of interest into the patient, non-viral gene therapy deploys an alternative delivery system for the gene of interest.

Examples for non-viral delivery systems include physical force to deliver the gene through the cell membrane; injecting the gene with a needle into the target region; electroporation, which uses an electric current to produce pores in the cell membrane through which the gene can be inserted into the cell; and chemical vectors, such as lipid-, polymer-, or peptide-based particles.

Nevertheless, viral vectors, such as the AAV, remain the preferred path for most companies. The efficiency of delivery for non-viral vectors remains questionable. This means that there might be reactions in the immune system that get triggered, eliciting a dangerous, adverse response. AAVs, on the other hand, are well-engineered and safe, despite being novel.

Viral vectors have recently demonstrated success, Krishnan adds. Scientists are making advances in the non-viral area of gene therapy but they also come with a unique set of challenges. Questions, such as how do they interact with serum components in the body, how do they involve the immune system before reaching the target tissue, how do they interact with the surfaces of cells, remain.

Despite unaddressed challenges, gene therapy has definitely shifted from being a hope to carrying an expectation. This is reflected in the number of investments pouring into the sector.

Big pharma and biotech companies are heavily investing their resources into gene therapy, Krishnan says. Typically, companies have vaccines or mAbs in their portfolio. Now, gene therapy is becoming a major modality of interest as well.

While we are still far away from reaching the smooth manufacturing processes we have in place for antibodies, many companies are also looking into platform approaches for gene therapy. We would take a quantum leap if we developed a platform approach for upstream and downstream processes. That would significantly reduce the time to the clinic. Platform approaches are definitely being explored, Krishnan adds.

Vendors like Merck are playing a big role in developing fit-for-purpose products for gene therapies, Krishnan says. At the R&D level, researchers are also working on advances in capsid engineering. We already have synthetic capsids, and there are other tremendous advancements in capsid engineering, design, and purity, which are going to continue to evolve.

But, as Krishnan puts it, We are running a marathon at sprint speed. The journey is exciting and challenging, identical to the ride on a rollercoaster, but we are barely even at the tip of the iceberg. There are patients waiting for life-saving treatment, so gene therapies will definitely continue to be in the limelight, and for good reason.

Are you fighting to solve the bottleneck in viral vector production? Get in touch with the expert team at Merck and view their webinar on this topic!

*The life science business of Merck operates as MilliporeSigma in the U.S. and Canada.

Images via Shutterstock.com and Elena Resko

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Dive Brief:

Like other CDMOs, Thermo sees a massive opportunity in the field of gene therapy.

Thermo paid $1.7 billion last year to buy viral vector contract manufacturer Brammer Bio. The company later opened a $90 million manufacturing facility in Lexington, Massachusetts, and it's expanded capacity at sites in Cambridge, Massachusetts, and Alachua, Florida, as well.

Thermo's new space in Massachusetts will rival a 300,000-square-foot plant operated by Swiss drug manufacturer Lonza in Pearland, Texas, outside of Houston. Lonza called the plant the world's largest dedicated to cell and gene therapy production when it opened in 2018.

Lonza has also been steadily making deals in an effort to support biotech and pharma customers through every step of the process in gene therapy. As of April 2019, the company had worked with more than 45 viral vector customers and expected that number to keep climbing.

Other companies are expanding, too. Fujifilm in November announced plans to spend about $120 million in the gene therapy field, including a new innovation center in Texas. Catalent last year paid $1.2 billion for Paragon Bioservices to bolster its manufacturing capacity for gene therapies.

Thermo said its new plant will take advantage of the latest technology, with digital connectivity and advanced operator training. The company said it chose to construct the site in Plainville to take advantage of nearby Thermo facilities and draw on the Boston-area talent pool

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Thermo Fisher to invest $180M in new gene therapy plant - BioPharma Dive

California-based Kriya Therapeutics announced on Tuesday that it concluded an $80.5 million Series A financing round, led by QVT, Dexcel Pharma, Foresite Capital, Bluebird Ventures, Narya Capital, Amplo, Paul Manning, and Asia Alpha. The company, which was founded in 2019, has a pipeline that includes multiple AAV-based gene therapies for the treatment of type 1 and type 2 diabetes, as well as obesity.

"There have been numerous successful gene therapies focused on rare monogenic diseases in recent years," said Shankar Ramaswamy, M.D., Co-Founder, Chairman, and CEO of Kriya Therapeutics. "We see tremendous potential to expand the field and apply gene therapy to highly prevalent serious diseases. We are focused on designing gene therapies using algorithmic tools, scalable infrastructure, and proprietary technology to optimize the efficacy and durability of our treatments. We look forward to accelerating the development of our pipeline, platform technologies, and internal GMP manufacturing capability with the funds raised in this Series A financing."

Kriya focuses on developing gene therapies for conditions that impact millions of patients. Its goal is to design one-time gene therapies to express therapeutic proteins within specific human tissues. Kriyas pipeline includes KT-A112, KT-A522, and KT-A832, all of which are investigational gene therapies.

Kriyas leadership team is composed of experts who have experience designing, developing and manufacturing successful gene therapies as well.

"Kriya is building a leading team and cutting-edge infrastructure to engineer best-in-class gene therapies for severe chronic conditions and accelerate their advancement into human clinical trials," said Roger Jeffs, Ph.D., Co-Founder and Vice Chairman of Kriya. "The company is committed to incorporating the latest advancements in the field into the design and development of its therapeutic constructs. Through its R&D laboratory capabilities in the Bay Area and in-house process development and manufacturing infrastructure in Research Triangle Park, I believe that Kriya will be uniquely positioned to become a leader in the gene therapy field."

Another company with a focus on gene therapy that recently came out of stealth mode is Dyno Therapeutics. On Monday, the Massachusetts-based organization announced that it is now eligible for more than $2 billion in upfront payments, research support and various milestones and options fees through its research-and-development and collaboration deals.

Dyno, which launched in 2018 with approximately $9 million in financing, has a technology platform built on the intellectual property that came from the laboratory of George Church. Church, who is the Robert Winthrop Professor of Genetics at Harvard Medical School, is a cofounder of Dyno.

At Dyno, we see a vast opportunity to expand the treatment landscape for gene therapies, said Eric D. Kelsic, co-founder and chief executive officer of Dyno. The success of gene therapy relies on the ability of vectors to safely and precisely deliver a gene to the intended target cells and tissues. Our approach addresses the major limitations of naturally occurring AAV vectors and creates optimized, disease-specific vectors for gene therapies with great curative potential. Our portfolio of R&D programs and newly-announced collaborations with leading gene therapy developers reflect the applicability of our AI-powered approach to improve treatments for patients and expand the number of treatable diseases with gene therapies.

Dyno has announced partnerships with Novartis and Sarepta Therapeutics thus far. With Sarepta, Dyno will design and discover novel AAV capsids to improve gene therapy for muscle diseases. Along with Novartis, Dyno will focus on developing improved AAV vectors for gene therapies for ocular diseases.

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Kriya Therapeutics to Focus on Gene Therapy with $80.5M in Funding - BioSpace

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Cutting-edge research on rewriting the genes responsible for Tay-Sachs disease, sickle-cell anemia, and other disorders will be presented at this weeks online annual meeting of the American Society for Gene and Cell Therapy. Originally planned as a Boston gathering, the scientific groups get-together became a virtual one because of the Covid-19 pandemic.

From Tuesday through Friday, academic researchers will be presenting their latest data online, along with updates from firms like Bluebird Bio (ticker: BLUE), Voyager Therapeutics (VYGR), Fate Therapeutics (FATE), Beam Therapeutics (BEAM), Axovant Gene Therapies (AXGT), and many others. Patients and their families have found their way to clinical trials through the societys website.

Bluebird plans presentations on its cell therapy against the blood cancer known as multiple myeloma. Using a technology known as CAR-T, the company creates supercharged versions of a patients immune cells that have halted disease progression in some of the 18 patients enrolled in a continuing Phase 1 trial.

Featured on Friday will be reports on the first babies treated with gene therapy for the debilitating neurodegenerative disorder Tay-Sachs. The treatment is being developed by the London-based Axovant under license from the University of Massachusetts Medical School.

Voyager will discuss its preclinical mouse studies on treating neurological disorders like amyotrophic lateral sclerosis and Huntingtons disease by using techniques that block the rogue signals generated by defective genes.

Fate Therapuetics is scheduled to show a new off-the-shelf CAR-T technology that it hopes will allow the immune system to target a broad range of solid tumors as well as multiple myeloma. The approach is licensed from Harvard Universitys Dana-Farber Cancer Institute.

Beam, meanwhile, will detail success it has shown in preclinical editing of the genetic defect that causes sickle-cell anemia. The company is developing a sharper-edged way of rewriting faulty genes than the widely used Crispr technology that Beam licensed from researchers at the Broad institute of Harvard and MIT. Beam founder and Crispr pioneer Feng Zhang will give a featured lecture as part of the online meeting on Thursday.

Write to Bill Alpert at william.alpert@barrons.com

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Gene-Therapy Treatments for Tay-Sachs, Sickle Cell to Be Featured in Online Gathering - Barron's

Japan's national health insurance will cover a gene therapy drug for a rare childhood genetic disorder that costs 167 million yen ($1.56 million) per treatment, making it the most expensive medication funded by the public system, government officials said Wednesday.

An advisory panel to the health minister approved provision of Swiss pharmaceutical giant Novartis AG's drug Zolgensma for spinal amyotrophy patients under the age of 2 starting as early as May 20, the officials said.

The drug, which costs over 200 million yen in the United States, is known as the world's most expensive medication.

Supplied photo shows samples of Swiss pharmaceutical giant Novartis AG's gene therapy drug "Zolgensma" for spinal amyotrophy patients. (Photo courtesy of Novartis)

It is a one-time therapy for the genetic disorder, which causes motor neuron loss and muscle wasting, and its coverage by insurance will offer hope for patients of the disease and their families.

With Japan's social security expenses ballooning amid the rapid aging of its population, some experts have expressed concerns over the burden on the insurance system of inclusion of the treatment. They also note that new drugs have tended to be highly expensive in recent years.

But a senior health ministry official said that given the small number of patients of the rare illness, "the fiscal impact is going to be limited."

The previous most expensive drug in Japan was Kymriah, approved last May to treat leukemia and other hematologic cancers, at 33.49 million yen.

Novartis Pharma K.K., a Tokyo-based unit of the Swiss pharmaceutical company, produces and sells both Kymriah and Zolgensma.

Spinal amyotrophy affects one or two infants out of every 100,000 and can lead to severe respiratory problems and early death. Without use of an artificial respirator, it is said that most die within 18 months.

Zolgensma will be given as a one-time infusion into the vein, which can introduce normal genes into human cells to recover motor function.

Novartis expects that the drug will be administered to about 25 patients per year in Japan, estimating annual sales of 4.2 billion yen.

Under the Japanese insurance system, out-of-pocket medical expenses for those under 2 are set at 20 percent of the total. But the real payment is minimal as the central and municipal governments cover almost all the expense under subsidy programs.

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Japan's health insurance to cover $1.5 million gene therapy drug - Kyodo News Plus

Sarepta Therapeutics Inc. andDyno Therapeutics Inc., have announced an agreement to develop next-generation Adeno-Associated Virus (AAV) vectors for muscle diseases, using Dynos CapsidMap platform. Dynos proprietary CapsidMap platform opens up new ways to identify novel capsids the cell-targeting protein shell of viral vectors that could offer improved muscle targeting and immune-evading properties, in addition to advantages in packaging and manufacturing.Our agreement with Dyno provides us with another valuable tool to develop next-generation capsids for gene therapies to treat rare diseases, saidDoug Ingram, Sareptas president and CEO. By leveraging Dynos AI platform and Sareptas deep expertise in gene therapy development, our goal is to advance next-generation treatments with improved muscle-targeting capabilities.Under the terms of the agreement, Dyno will be responsible for the design and discovery of novel AAV capsids with improved functional properties for gene therapy and Sarepta will be responsible for conducting preclinical, clinical and commercialization activities for gene therapy product candidates using the novel capsids. If successful, Dyno could receive over$40 millionin upfront, option and license payments during the research phase of the collaboration. Additionally, if Sarepta develops and commercializes multiple candidates for multiple muscle diseases, Dyno will be eligible for additional significant future milestone payments. Dyno will also receive royalties on worldwide net sales of any commercial products developed through the collaboration.This agreement is a major step forward in our plan to realize the potential of Dynos AI platform for gene therapies to improve patient health. We are excited to work with Sarepta to create gene therapies with improved properties to address a range of muscle-related diseases, stated Dynos CEO and co-founderEric D. Kelsic, Ph.D. The success of the gene therapies developed through this collaboration with Sarepta will rely on AI-powered vectors that allow gene therapies to be safely and precisely targeted to the muscle tissue.

By designing capsids that confer improved functional properties to Adeno-Associated Virus (AAV)vectors, Dynos proprietary CapsidMap platform overcomes the limitations of todays gene therapies on the market and in development. CapsidMap uses artificial intelligence (AI) technology for the design of novel capsids, the cell-targeting protein shell of viral vectors. The CapsidMap platform applies DNA library synthesis and next-generation DNA sequencing to measureinvivogene delivery properties in high throughput. At the core of CapsidMap are advanced search algorithms leveraging machine learning and Dynos massive quantities of experimental data, that together build a comprehensive map of sequence space and thereby accelerate the discovery and optimization of synthetic AAV capsids.

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Sarepta And Dyno Therapeutics Will Develop Next-Gen Gene Therapy Vectors - Contract Pharma

People who are overweight and suffering from joint pain caused by osteoarthritis are often reluctant to exercise, even though physical activity can boost muscle strength and relieve pain. A new study suggests gene therapy may someday be a good option for those peopleand it may help them shed pounds, too.

Researchers at the Washington University School of Medicine gave young mice a single injection of the gene that makes follistatin, a protein that normally blocks another protein called myostatin, which modulates muscle growth. The therapy caused a significant buildup of muscle mass in the mice while also preventing obesity, the team reported in the journal Science Advances.

We've identified here a way to use gene therapy to build muscle quickly, said senior investigator Farshid Guilak, Ph.D., professor of orthopaedic surgery and director of research at Shriners Hospitals for Children St. Louis, in a statement. It had a profound effect in the mice and kept their weight in check, suggesting a similar approach may be effective against arthritis, particularly in cases of morbid obesity."

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In fact, the mice didnt just build muscle, they also nearly doubled their strength without exercising any more than they usually did. Despite being fed a high-fat diet, they had fewer metabolic issues and stronger hearts than did animals that did not receive the follistatin gene. Their joints were healthier, with less cartilage damage and inflammatory markers than their untreated counterparts, the researchers reported.

Whats more, the Washington University team discovered that the gene therapy promoted the beiging of white fat, meaning it turned some unhealthy white adipose tissue into brown fat, which positively correlates with increased triglyceride clearance, normalized glucose level, and reduced inflammation, the researchers wrote in the study. Therefore, delivering the follistatin gene could serve as a very promising approach to induce beiging of [white adipose tissue] in obesity, they wrote.

RELATED: Could gene therapy be the solution to obesity and diabetes?

This is not the first time gene therapy has been proposed as a potential treatment for obesity and other metabolic diseases. Australian researchers demonstrated that removing the gene RCAN1 from mice, for example, helped turn white fat into brown fat. And a team in South Korea used the gene editing system CRISPR to remove the FABP4 gene from mice that had been fed a high-fat diet, resulting in a 20% loss of body weight and a reduction in insulin resistance.

The Washington University teams approach is distinctive in that it focuses on building muscle. But the researchers noted theyll have to do further studies to determine whether the gene therapy has any negative effect on heart muscle. Even though heart health improved in the mice, any thickening of the hearts walls could be dangerous over time.

Still, Guilak and his colleagues believe that follistatin gene therapy could be a promising approach to treating several conditions, including muscular dystrophy and other diseases that cause muscle wasting, they said in the study.

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Gene therapy cuts fat and builds muscle in sedentary mice on unhealthy diets - FierceBiotech