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Scaling up gene therapy to address global commercialization challenges

Former President & CEO

Geoff MacKay | Former President & CEO

With clinical success, all eyes turn to gene therapy manufacturing and commercialization challenges

Cell and gene therapies are here to stay as a new class of life-changing medicines. They recently headlined the fiscal year report issued by the FDA’s Center for Biologics Evaluation and Research (CBER), in which CBER Director Peter Marks prominently noted, “FY 2018 was particularly exciting because of the pace of progress in cellular and gene therapies. CBER received more than 150 INDs for gene therapy products, bringing the total number of active INDs up to nearly 800 applications.1

Dr. Marks has been outspoken about what’s needed for the next stage of gene therapy. He has written, “For gene therapy, the quantum leap that I would expect in the next five years or so is solving the issue of manufacturing. This is needed to continue advancement of the field and to allow it to reach a broader range of patients.”2

I couldn’t agree more.  In fact, from the very first moment we formed AVROBIO in 2015, our raison d’être was to take ex vivo lentiviral gene therapy mainstream, first line, to industrialize it. We set our sights well into the future. I believe this longer-term vision is necessary for any gene therapy company that wants to create meaningful, sustainable value.

Like other gene therapy biotechs, our technologies and programs had their roots in academia. As AVRO has grown, we have focused on optimizing our vector and manufacturing systems with the expectation that they may become a commercial stage platform that can support the potential development of treatments for multiple diseases.  We call this platform plato®.

Beginning-to-End Integration

The plato platform has focused our attention on refining, and locking in, a set of process changes that seek to optimize the potential potency, efficacy and durability of our investigational gene therapies and solving the downstream operational bottlenecks.  For any gene therapy process, we believe the rigor of evaluating and integrating every step in the product commercialization process is required for mainstream market success.  We view this as beginning-to-end integration.

Putting Strategy into Practice

It’s a well-known fact that there are bottlenecks and barriers to manufacturing and commercializing gene therapies. It’s a big step to take something that’s really bench science – petri dish science – that can enable a lab procedure to treat one patient and turn it into a process for creating medicines for thousands of patients.  This transition to industrializing gene therapy is what Dr Marks suggests is needed now.

How is it possible to tease apart all the elements and complexities of commercializing gene therapy to build a beginning-to-end process?

The 3 Major Challenges

As a case in point, let me describe our approach building plato over the past three and a half years.  Essentially, we identified three historic bottlenecks or hurdles in developing gene therapies. Then, we steadily built plato to include proprietary or industry-leading solutions to enable optimization, integration, and scale with the goal that AVRO becomes a multi-product gene therapy leader. We build one platform that’s designed to be applied across our portfolio:

Challenge 1:  Developing a high-performance vector that’s a product engine

For every gene therapy developer, the vector is fundamental because it defines many performance characteristics.  It’s important to invest in vector design as early as possible.  For AVRO, plato includes our proprietary,  state-of-the-art, four-plasmid lentiviral vector system, called LV2, that is designed to be produced in a commercial-scale process.

At the outset of developing LV2, we envisioned a common vector that could be used throughout our portfolio of investigational gene therapies for a class of rare diseases, called lysosomal storage disorders. We integrate proven, best-in-class components into LV2, meaning the components have been previously successful in the clinic. Technical improvements include potentially enhanced safety by moving from a three- to four-plasmid system, streamlining the four plasmids to increase titer, and enhancing transgene transcription and translation, to increase in vivo enzyme production for a given promoter. All of the upgrades are designed with the goal to enhance safety while increasing efficacy and “manufacturability.”

With plato, our lentiviral vector design is standard and flexible in that it can accept different genes in order to meet the requirements for different diseases. In this way, it is a true producer engine for multiple investigational lentiviral gene therapies.  For example, the proven features of our first gene therapy for Fabry disease is designed to be quickly and easily leveraged for the next gene therapies in our pipeline for other lysosomal storage disorders, including Gaucher disease, cystinosis and Pompe disease.

With a common vector for our products, we believe there are some clear and compelling benefits, and I’ll note a few:

  • rapid expansion to new pipeline ideas;
  • low technical risk and higher probability of success for new product candidates;
  • leverage safety profile of a known, “regulatory compatible” vector backbone;
  • operational synergies across CMC functions.

Challenge 2:  Supply chain excellence to secure availability of critical raw materials and seamless patient experience

Managing all the steps in a complex supply chain is critical, especially for ex vivo lentiviral gene therapy which uses each individual patient’s cells.  In building plato, a central premise was to be streamlined and efficient throughout the entire process: from the initial point of gene therapy production, which in our case is collecting a patient’s cells, to delivering the final gene therapy product at the point of administering the medicine to the patient. The goal is to make the patient experience seamless and convenient, and securing the availability of critical raw materials so that the gene therapy is delivered to the patient reliably every time.

One of the first supply chain challenges that we addressed with plato was to produce vector at scale. We recognized that we needed to be able to do what the field of monoclonal antibodies did decades ago, which was to scale up a complex new medicine in large bioreactors. For us and any gene therapy company, producing vector at scale is essential in order to accommodate multiple clinical trials, as well as ultimately to supply commercial product. The ability to manufacture vectors at scale converts the vector into what it should always be: a long-lead time, critical raw material, but nothing more.  In our case with plato, our vector is produced in a 200-liter serum-free suspension bioreactor, producing high-titer vector.

There are other aspects of rigorous supply chain management which the plato platform addresses.  One important technical feature is optimizing the cryopreservation process to enable longer shelf life and convenient scheduling for patients, while still maintaining viability post-thaw. The fastidious attention to the supply chain is something that we consider to be an essential component of plato, and a critical competency for our potential future commercialization. 

Challenge 3: Commercial-scale manufacturing that’s ‘closed and compact,’ instead of ‘bricks and mortar’

In the early days of ramping up of gene therapy, the predominant manufacturing strategy has been to invest in “bricks and mortar” involving the building of large, centralized facilities.  These manufacturing facilities cost tens or hundreds of millions of dollars to build and require the highest levels of clean room standards.  They were justified because of the shortage of bioprocessing capacity and the huge fear of capacity shortages leading to major delays.  Worse than the upfront costs have been the ongoing operational drain of sustaining quality teams while demand is low and/or inconsistent.

With plato, AVRO has taken a markedly different approach to redefining gene therapy manufacturing. Rather than focusing on the bricks and mortar, we focus on the critical cell bioprocessing steps.  In lieu of “bricks and mortar,” we utilize a “closed and compact” automated manufacturing system with a 3-day process. This allows us to quickly and reliably open up manufacturing in multiple locations across the world.  Our vision for commercialization is to have three manufacturing facilities that service worldwide demand, one in the US, one in the EU and one in Asia Pacific. We are already active in each of these regions and prepping for anticipated eventual commercial demand.

Rather than large factories and high-grade cleanrooms, our approach addresses gene therapy manufacturing with technology innovation.  We believe that this approach is ideally suited to the manufacturing needs for ex vivo lentiviral gene therapies, where the supply chain involves the cells of individual patients.

To our knowledge, plato represents the first clinical-stage, automated, closed manufacturing system for CD34+ gene therapies.   In future blogs I will highlight various performance features in greater detail:

  • Automation of manufacturing units is flexible across geographies around the world. plato enables manufacturing at scale in closed, automated devices that can operate in any geography around the world. This gives us flexibility and portability, so we can meet anticipated demand in the continent or country where patients live.
  • Proprietary AVRO algorithms are optimized. With plato, we have programmed our proprietary algorithms into the devices, optimized so that manufacturing procedures are consistent from patient to patient and between CMOs.
  • Standardized units can yield high GMP quality and consistency, eliminating inter-operable variability. The automation of plato’s manufacturing system is designed to greatly reduce the need for skilled technicians and avoid human error and inconsistency.
  • Industrializing helps create cost efficiencies. An automated, standardized manufacturing system helps to deliver product with a well-defined fixed and variable cost.

Overall, plato’s automated, closed cell manufacturing system is key to our ability to commercialize our gene therapies worldwide for multiple products.

Taking the quantum leap

Entering 2019, AVRO’s highest priority was to secure regulatory clearances enabling the use of plato in multiple trials in multiple countries, including Australia, Canada and the U.S. Those regulatory clearances have now been achieved. We anticipate this will allow us to begin integrating plato into our clinical trials in the second half of 2019.

Like many of our cell and gene therapy peers, we are intensely focused on manufacturing scale-up and commercialization. plato represents our quantum leap and the realization of our vision to be world-class at designing, developing and commercializing ex vivo lentiviral gene therapy products.  It’s taken our team’s tremendous resolve and commitment from day one to get to the point where we can now say with confidence that AVRO is “powered by plato.”


  1. S. FDA, Center for Biologics Evaluation and Research (CBER) FY2018 Report from the Director, April 19, 2019.
  2. McKinsey & Company, Helping to accelerate cures: Regulating the rapidly evolving field of cell and gene therapies, Interview with Peter Marks of FDA, January 2019.



This blog contains forward-looking statements, including statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding AVROBIO’s business strategy, prospective products and goals, the therapeutic potential of our product candidates, and anticipated benefits of our gene therapy platform including potential impact on our commercialization. Any such statements in this blog that are not statements of historical fact may be deemed to be forward-looking statements based on current expectations, estimates and projections and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. For a discussion of these and other risks and uncertainties, see the section entitled “Risk Factors” in AVROBIO’s Annual Report on Form 10-K for the fiscal year ended December 31, 2018, as well as discussions of potential risks, uncertainties and other important factors in AVROBIO’s subsequent filings with the Securities and Exchange Commission.