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A Year of Promise: Five Key Gene Therapy Developments to Watch in 2020

Geoff MacKay

Geoff MacKay | President and Chief Executive Officer

The new year always brings new promise – and that’s certainly true in our fast-moving field of gene therapy.

We saw some tremendous advances last year, such as regulatory approvals of two new therapies – as well as several less splashy developments worth keeping an eye on. I have high hopes that the field will progress even faster in 2020. Here are five developments that I’ll be watching closely:

New approaches to conditioning

The new year holds the promise of bringing exciting advances in conditioning the bone marrow niche to enable the necessary space for successful CD34+ engraftment.

At the recent annual meeting of the American Society of Hematology (ASH), Magenta Therapeutics shared encouraging preclinical data on an investigational antibody-drug conjugate that’s intended to be a gentler alternative to current conditioning regimens. Another important presentation came from Forty Seven, which shared data suggesting that their investigational drug significantly depleted hematopoetic stem cells in bone marrow, with no dose-limiting toxicities.

Conditioning is an essential step in transplant therapies to treat many blood disorders; it’s also crucial to ex vivo gene therapies. The ex vivo process involves collecting a patient’s stem cells, transducing them in the lab with a therapeutic transgene, and then infusing them back into the patient with the goal of producing a durable supply of the functional protein the patient needs. If the treatment is to be effective in the long term, the therapeutic cells must engraft. Conditioning clears space in the bone marrow for CD34+ cell engraftment, and potentially in some cases in the central nervous system for microglia derived from the CD34+ cells to repopulate the brain.

At my company, AVROBIO, we are proud of our personalized conditioning program for our investigational gene therapies. We use a protocol called therapeutic dose monitoring (TDM) to assess how each patient is metabolizing the conditioning agent so the dose can be adjusted to suit the patient’s needs. Based on data from hundreds of patients who have undergone conditioning for various therapies, we seek to maximize the chance of engraftment while minimizing side effects. In the future, we also hope to give patients and physicians more opportunities to select the conditioning regimen they feel is right for them. Yet even with this level of personalization, there can be unpleasant side effects to these medications, in part because they temporarily depress the patient’s immune system.

That’s why it’s terrific to see industry pioneering new approaches.

Magenta’s investigational drug, for instance, is an antibody-drug conjugate (ADC) in which the antibody is engineered to hook on to a specific receptor, CD117 (c-KIT), found only on stem cells in the bone marrow. When it binds to CD117, the antibody is internalized together with its cytotoxic payload (amanitin) and destroys the stem cell, thus clearing space for the future engraftment of therapeutic cells. Because this approach precisely targets stem cells, it should (in theory, at least) have fewer side effects than traditional conditioning regimens.

We’ll be looking forward to hearing more about conditioning alternatives from both Magenta and Forty Seven, as well as new players joining the field.

Deeper insights into stem cells

Scientists have been exploring the power of hematopoietic stem cells for more than five decades; lately, the pace of discovery has rapidly increased. I believe we’re on the cusp of new insights that could dramatically increase the utility of these cells in a wide array of therapeutic modalities, including the ex vivo lentiviral gene therapies we’re developing at AVRO.

Many of us are keenly interested in particular in unlocking the potential of CD34+ cells, which produce progenitor cells that mature and differentiate into all the components of the healthy blood and immune system. Gathering sufficient numbers of functional CD34+ cells can be an expensive challenge, so it was exciting to see a paper published last summer in Stem Cell Research & Therapy which demonstrated a novel method for expanding populations of enriched human CD34+ cells with a cost-efficient growth medium the authors dubbed HEM (hematopoietic expansion medium).

We are also seeing innovative ideas come from companies like Gamida Cell, which presented data at ASH about using an allosteric inhibitor of NAD-dependent enzymes, nicotinamide, to better preserve the functionality of CD34+ stem cells for bone marrow transplants through the expansion process. I’m looking forward to watching these and other initiatives blossom in 2020.

I’m especially eager to see more progress on technical fronts, such as the development of new methods to identify whether transplanted stem cells have successfully engrafted. It can now take more than a year to be fully confident that transplanted cells have engrafted and are durably producing generations of daughter cells. If we could compress that time frame – as seems quite possible – we believe we could develop therapies faster while giving patients and their doctors earlier visibility into the outcomes of their treatment. This has tremendous practical implications for both stem cell transplantation and ex vivo gene therapy.   

Building a better supply chain

This next development may sound dull, but it’s essential for the successful maturation of gene therapy. It’s about initiatives from companies like Vineti and Be The Match BioTherapies focused on customizable platforms that help gene therapy developers build, nurture and exert strict quality control over their supply chains.

Cell and gene therapies are incredibly complex to produce, with a long and winding supply chain. I sometimes think of our collective efforts in this industry as analogous to Tesla’s work supporting the launch of its electric cars. Designing a sleek and efficient vehicle wasn’t enough; Tesla also had to build a nationwide network of charging stations, train mechanics to service electric cars, and educate a much wider stakeholder base about their potential. Similarly, we in the gene therapy industry can’t be content to simply engineer powerful therapies in the lab. Ensuring patient access across the world is a complex and evolving puzzle we’re all building together.

At AVRO, we continually remind ourselves that we are not just developing drugs; we’re developing a global infrastructure to support and care for people in need. For example, when therapeutic dose monitoring is used to customize a patient’s conditioning experience, we need a lab nearby with the expertise to analyze the patient’s blood samples in real time – and provide fast, accurate results. Not every hospital or commercial lab is equipped to do these analyses, much less on an expedited timetable. We’ve had meetings dedicated solely to poring over maps to figure out how quickly we can get a sample to a qualified lab so that physicians can adjust the next conditioning dose with the precision our patients deserve.

That’s why it’s good to see initiatives like the Accellerate Summit. Held last summer, it was a day-long event that brought together industry, apheresis centers, clinicians, patient advocates and others to talk through the high demands placed on supply chains – and to brainstorm potential solutions. Stakeholders who attended that summit are now working on a white paper to outline how we might standardize protocols at various steps along the path from the initial cell collection to the delivery of a personalized therapy.

Investing in a truly global future for gene therapy

In October, the Bill and Melinda Gates Foundation and the National Institutes of Health announced a $200 million commitment toward bringing gene therapies for diseases such as sickle cell and HIV to the developing world.

In order to bring down costs and scale up production, we will have to bring more automation to gene therapy development and manufacturing. Nonprofit investment towards this goal will likely produce a halo effect of technologies applicable to other platforms and indications.

We can’t expect tangible results immediately, of course, but our common goal should be to develop medicines which are accessible for everyone, regardless of where they are born.

Training the next generation of talent

We need many more experts, and quickly!

I can’t put it more plainly than that. Referencing AVRO as a microcosm of our industry, we anticipate almost doubling in size, to 150 full-time employees, in 2020. So, I’ve been encouraged in recent years to see the emergence of specialist gene therapy training programs to supply a field growing by leaps and bounds. We need many more scientists, engineers, clinicians, program managers, patient advocates and just about every other job title you can imagine.

The common thread across each of these topics is an industry which is maturing, reaching commercial stage and becoming mainstream. The focus is less on demonstrating proof-of-concept and more on solving bottlenecks so that gene therapies may become standards of care across a fast-expanding list of disease targets. Now let’s roll up our sleeves and make it happen.


Geoff MacKay is President and Chief Executive Officer of AVROBIO, Inc. AVROBIO is currently conducting clinical trials to evaluate the safety and efficacy of its investigational ex vivo lentiviral gene therapies. None of these investigational gene therapies has been approved by the U.S. Food and Drug Administration or any other regulatory agency. For more information, go to www.avrobio.com.