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Taking flight: Gene therapy ascending

Former President & CEO

Geoff MacKay | Former President & CEO

The gene therapy field is ready to soar into a new era. This is a pivotal moment and there is clearly a tail wind at our back. Our sights are set on developing gene therapies to deliver dramatic impact, and even cures, for patients.

Our name, AVROBIO, is inspired by cutting edge aeronautical innovation from the 1950’s, the avant-garde Canadian fighter jet AVRO Arrow. It truly represented technology ahead of its time.  In some ways, there’s a similarity between what’s happening in our industry now and the early days of the aviation industry.

While the Wright brothers were the first to make a sustained, controlled, powered, heavier-than-air manned flight in 1903, it took decades of consistent, incremental innovation for air travel to become economical, routinely safe, and mainstream. In the 1950s, often referred to as the “golden age” of air travel, commercial airlines emerged with regularly-scheduled flights and routes, so that airline travel began to reach the masses. By 2018, decades of advances in design, manufacturing, and safety features have brought the benefits of air travel to a mass market—with commercial airlines carrying four billion passengers worldwide each year.

It seems that we are approaching the “golden age” of gene therapy. Currently, there are more than 300 gene therapy clinical trials ongoing.  The fact that the number of gene therapy clinical candidates is estimated to exceed the number of monoclonal antibodies in clinical development is an astounding statistic.1, 2 The pace of innovation is accelerating as drug developers concurrently optimize potency and safety while beginning to take on the challenge of industrialization.

Pushing New Boundaries, Disease by Disease

In the quest to revolutionize travel, the aviation industry needed to push boundaries and focus on innovations across a multitude of fronts. That analogy holds true in our industry, as a number of academic labs and biotech companies work to chip away at key parameters in order to design gene therapies specifically tuned to the biology of targeted diseases.

While the early initiatives in gene therapy arose during the 1990s, it took until 2017—nearly three decades—for the first gene therapy to evolve from initial clinical trials to a full-fledged FDA approved product.

Advances continue to be driven by leading therapeutic companies like Bluebird, Novartis and Spark to name a few – coupled with enablers such as Miltenyi, GE, CCRM and Vineti. The experiences of these leaders are establishing a path and giving us a field of vision for optimizing gene therapy technology. Collectively, development and refinement of a host of new enabling tools, techniques and insights are solving historic bottlenecks.

Those of us developing gene therapies are both leveraging and adding to this collective wisdom as we apply know-how to specific diseases.  At AVROBIO, we are currently focusing on gene therapies for a class of rare diseases called lysosomal storage disorders. Others target oncology, ophthalmology, inherited blood disorders, primary immunodeficiencies, and several additional diseases. Boundaries are being pushed simply by opening up the big book of medicine and identifying genetic diseases with high unmet need which would benefit from the unique advantages of a potential single-dose, curative gene therapy.

Incremental Steps Toward the Mainstream

Let me offer examples of a few parameters that have opened up gene therapy, and set us on a course towards bringing breakthrough science into the mainstream:

  • Safety first. The first therapeutic gene transfer occurred in 1990, with a retroviral gene therapy administered to a four-year old girl with the severe immune deficiency ADA-SCID, in a landmark clinical trial directed by Dr. French Anderson at the NIH Clinical Center. So, you could say that this event nearly 30 years ago was almost a ‘Wright brothers moment’ for gene therapy. In spite of that initial milestone, the technology wasn’t yet ready to take off.  Retroviral gene therapy is in the same family as lentiviral (LV) gene therapy, with similar modes of action e.g. integrating therapeutic genes into the patient’s genome.  During the 1990s, the early developers of LV gene therapy addressed the primary safety challenges with the removal of HIV pathogenic genes. The LV vector systems evolved, and the third-generation LV vector – a four plasmid system and self-inactivated (SIN) approach – first reported in 1998 and reduced the risk of producing replication competent lentivirus.Potential safety hurdles were encountered by AAV gene therapy as well. Due to their design, the first AAV vectors were inherently contaminated with wild-type AAV. This hurdle was overcome with a major redesign of the AAV two plasmid system during the early 1990s. Achieving improved levels of assurances for the safety of gene therapy was a primary hurdle which needed to be overcome to trigger both investment and energy units to be applied towards creation of an industry.
  • Therapeutic functionality for different diseases. Beyond safety, gene therapy technologies required flexibility to be adapted to different diseases. For lentiviral gene therapies, pseudotyping with VSV-g became a game changer in the mid-1990s. VSV-g enabled switching out the HIV vector envelope to enable transduction of multiple cell types and not just CD4 cells. Since AAV does not have an envelope, the equivalent to pseudotyping for AAV is naturally-occurring AAV serotypes and AAV engineered with optimized capsids. Both enable targeting of specific tissues and can also identify novel AAV variants with reduced sensitivities to neutralizing antibodies.These advances in gene therapy vectors and delivery technology are akin to the engineering feats for airplanes which enabled sustained flight and high altitudes. Sir George Cayley is called the father of the airplane based on his pivotal innovations in the mid-1800s. His rigorous study of the physics of flight and aerodynamics led to the underpinnings for the Kitty Hawk flight in 1903. His insights enhanced lift from curving the wing surface, and defined the modern airplane’s configuration of fixed wing, fuselage and tail assembly.I could speculate that our industry’s version of Sir George may be Dr. Inder Verma at the Salk Institute, one of the pioneers of the lentiviral vector who established the foundation for gene delivery and harnessing viruses for the technology. Interviewed in 2005, Verma predicted that gene therapy “will affect everything, any disease. Every disease has a genetic component…It’s just a matter of learning the technology. Therefore, I think finding and looking for vectors and ways to do it is highly justified because there is no other technology in the world for every aspect of human health.” 3
  • Making the journey through manufacturing. For lentiviral gene therapy, innovation with VSV-g also propelled the field by enabling lentiviral vectors to be adequately robust for manufacturing, while enabling the essential increase in infectious titer by greater than two orders of magnitude. Gene therapy is a highly complex technology, and creating standardized manufacturing is a key factor for rolling out consistent and high quality product for both clinical grade and commercial uses.Today, I believe fully automated, closed system, cryo-preserved cell bioprocessing is the next revolutionary step in manufacturing for the leading lentiviral gene therapy companies. This should elevate quality while driving down costs and increasing global supply chain flexibility.As more gene therapies are developed, manufacturing remains an area ripe for innovation. It’s not uncommon for manufacturing strides to trail technology innovation. With airplanes, it took until the 1960s for key manufacturing achievements, such as the first small jet aircraft, the Learjet, to enter mass production in 1963 – selling 100 planes in two years – and the first wide-body turbofan-powered commercial airliner, the 747, produced by Boeing in 1969.

A Medical Revolution is in Flight

Ongoing incremental innovations are required to truly deliver on our mission to take gene therapy mainstream and impact the millions of deserving patients. What has changed, is that it no longer takes a visionary to see where this field is headed. Proof-of-concept is established – we have taken flight.

At Kitty Hawk, it wasn’t clear how airplanes would make a transatlantic flight or be mass produced, and yet industrialization happened because the ingenuity of an entire industry of dedicated engineers who mobilized to continually enhance outcomes.

We are now building the gene therapy industry on the shoulders of giants. Early achievements are important building blocks to refine new gene therapies. As these early brilliant scientists pass the baton to multiple developers of medicine, the expanded goal is to push gene therapy into the mainstream. That is our goal at AVROBIO, to develop first-line therapies with broad utility reaching tens of thousands of patients with lysosomal storage disorders, and eventually addressing other diseases.

In future blogs, I will outline some thoughts within our AVROBIO team on key parameters we focus on to take gene therapy mainstream. With our industry clearly in breakthrough mode, we have a responsibility to our patient community to collaborate and share collective wisdom as we are on the cusp of transforming medicine.


1 Alliance for Regenerative Medicine, Q2 Quarterly Data Report, Aug. 2018, https://alliancerm.org/wp-content/uploads/2018/08/ARM_Q2_2018_Web.pdf

2 MTS Report on Gene Therapy, Nov. 2017, http://www.mtspartners.com/wp-content/uploads/sites/2/2016/08/Gene-Therapy_Near-term-Revolution-or-Continued-Evolution_Part-1.pdf

3 Jacoby J. Interview with Dr. Verma. Gene Therapy (2005) 12, 950-953, http://www.nature.com/articles/3302528