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Moving gene therapy forward: Predictions for the next phase of development

Former President & CEO

Geoff MacKay | Former President & CEO

Gene therapy has encountered plenty of speed bumps in the past year, with companies across the industry dealing with safety issues, regulatory setbacks, chemistry, manufacturing and control (CMC) challenges and difficult questions over commercialization. AVROBIO has not been immune, as we recently deprioritized one of our clinical programs due to several factors, including emerging clinical data suggesting variable engraftment coupled with challenging market and regulatory dynamics.

These industry-wide developments might prompt some to forecast tough times ahead. Certainly, the financial health of our industry has been hit hard in the last 12 months. But as a veteran of biotech, I see a bright future for our industry. Our recent challenges force us to make difficult decisions and adjust our timelines, but they may also give us valuable knowledge about how to develop gene therapies and show us where the greatest potential lies.

In fact, the challenges faced by our industry today have prompted me to think back to my early industry days working at Novartis. We were in the field of solid organ transplantation, which has historical parallels to the current state of gene therapy. By the 1990s, the five-year survival rate for kidney transplant patients had risen dramatically to nearly 90 percent for those receiving an organ from a living donor[i], demonstrating the critical role of novel immunosuppression agents to save lives, and resulting in about 15,000 organ transplants performed in 1990.[ii] Miraculous? – yes, but still rough around the edges. Transplant recipients continued to experience complications because of required powerful, yet toxic, immunosuppressant medicines or preexisting comorbidities.

There followed a period of gradual progress, which focused our energy on reducing the harshness of the toxic triple drug immunosuppressive cocktails. We sought to maintain efficacy while striving to reduce post-transplant diabetes, hypertension, gingival hyperplasia and other comorbidities. As the medical community gained experience caring for post-transplant patients, the risk-benefit of these critical drugs improved incrementally. Today, the five-year survival rate for patients receiving a kidney from a living donor is about 93 percent.[iii] But more significantly, the number of organ transplants per year is about 40,000,[iv] limited only by the supply of donor organs.

Additionally, there is great hope on the horizon for people with organ transplants. Companies, such as Talaris Therapeutics, are in late-stage studies with what is hoped to be a step-change, innovative cell-based approach aiming to deliver freedom from immunosuppression. We may soon realize the dream of complete tolerance, significantly shifting the risk-benefit equation for patients.

In my mind, gene therapy is in a place once occupied by earlier approaches to solid organ transplant.

Multiple viral and non-viral gene therapy approaches are being developed with each displaying differing emerging safety profiles. Recently, at the U.S. Food and Drug Administration (FDA) Cellular, Tissue and Gene Therapies Advisory committee meeting held in September 2021, safety concerns around adeno-associated viral (AAV) gene therapy were debated in depth, including concerns about cancer, hepatotoxicity as well as hematological and neurological toxicity, causing experts to call for more transparency and better manufacturing standards. Significant efforts are being deployed in both academia and industry to potentially enhance the safety and tolerability of AAV gene therapy.

In this post, I would like to focus on some cutting-edge work being done with the goal to further enhance the profile of gene therapy using patients’ own hematopoietic stem cells (HSCs). I believe that these advancements have the potential to improve the risk-benefit balance and facilitate its future broad adoption across a growing list of monogenic diseases.

Deeper understanding of the science of HSC gene therapy

Refinements to enhance the safety of gene therapy require deep scientific knowledge, which is growing rapidly with discoveries in genomics, immunology and cell biology. These advances mean that we enter the clinic today with far more questions answered and issues resolved than we did 20 years ago. I expect to see the understanding of gene therapy at the cellular level continuing to expand in 2022.

Recently, scientists from AVROBIO, Harvard Medical School and the San Raffaele Telethon Institute for Gene Therapy in Milan shared data showing exactly where in the DNA sequence therapeutic genes had been inserted in treated progenitor cells and used those locations as identifiers to trace how transduced cells differentiated and divided over time. AVROBIO researchers also use single cell sequencing to characterize the gene therapy cell product from initial collection, through genetic modification and potentially for up to multiple years after treatment. This level of analysis may answer essential questions about certain safety features of HSC gene therapy, which we have never before had the capability to address. Read more about this here.

Improving the HSC gene therapy administration process

Over the course of 2022 and beyond, I also expect to see additional improvements in the necessary steps that precede or follow gene therapy infusions.

Conditioning, for example, has evolved considerably over recent years for ex vivo gene therapy. Conditioning agents are administered before the gene therapy itself to clear space in the patient’s bone marrow, space that is then expected to be taken up by the patient’s own genetically modified stem cells.

Today conditioning agents can be administered with greater precision to target a specific area-under-the-curve (AUC) exposure. This meticulous approach is designed to minimize out-of-range toxicity while clearing sufficient space to allow for potential engraftment of the genetically modified stem cells. Ongoing science may serve to further improve this essential conditioning step. New investigational conditioning agents being developed by companies like Magenta Therapeutics and Jasper Therapeutics are anticipated to interact with external signals that tell stem cells to maintain themselves. For example, without an incoming “stay alive” signal, stem cells undergo a preprogrammed cell death. These potential conditioning agents are increasingly moving into the clinic, and 2022 may see clinical data that could further expand conditioning agent options available to physicians and patients in the future. Of course, if the tolerability profile of the concomitant conditioning step can be further refined, the overall benefit of ex vivo gene therapy could be enhanced.

Building robust, automated platforms

Finally, to help reduce the potential for regulatory and CMC delays and improve standardization across clinical trials, I expect that we will increasingly see gene therapy companies investing in technology platforms able to support new indications in a modular fashion. A robust CMC platform designed with safety, platform synergies and scalability in mind has tremendous potential because it is intended to efficiently and cost-effectively deliver a consistent drug product.

Central to that progress is automation, which has the potential to add reliability, consistency and process quality. Manual processes are labor intensive, complicated and expensive. They require rigorous ongoing workforce training and qualification. And importantly, these challenges become more profound as volume and scale increases. Automation may make it easier to add manufacturing sites, which will ultimately facilitate commercial scale out. I believe that we will see an increasing trend toward platform standardization and automation in 2022 and beyond.

I believe that all three of these advancing trends — deeper scientific understanding, treatment process innovations and platform development — are pushing gene therapy along a well-worn path that has been followed by not just organ transplantation but cancer immunotherapy, in vitro fertilization and other medical innovations. What once seemed impossible, eventually becomes routine.

In 2022 and beyond, we will see even more gene therapies going into the clinic, and companies will work to further refine vectors, conditioning regimens, manufacturing and other components of the process as we progress towards the goal of making gene therapy a mainstream medicine. We can’t expect gene therapy to be as routine as swallowing a capsule, but no one ever expected that for organ transplantation either – and look how far that has come. It’s up to us as an industry to lead the way.


[i] Briggs, J. Douglas (2001). Causes of death after renal transplantation. Nephrology Dialysis Transplantation 16 (8) 1545-1549. doi: 10.1093/ndt/16.8.1545

[ii] United Network for Organ Sharing data. https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/#

[iii] Hariharan, S. et al. (2021). Long-term survival after kidney transplantation. NEJM. 385(8), 729-743. Supplementary Table 1. doi: 10.1056/NEJMra2014530

[iv] United Network for Organ Sharing (2021). All-time records again set in 2021 for organ transplants, organ donation from deceased donors