Guest Column | June 2, 2020

From Hope To Reality: The Potential Of Hematopoietic Stem Cell Gene Therapy In Rare Diseases And Beyond

By Bobby Gaspar, M.D., Ph.D., CEO of Orchard Therapeutics


August 1992 was a pretty important time for me, as that is when my journey in the field of gene therapy began. I had just started as a junior doctor at Great Ormond Street Hospital for Children in London, and it was my first opportunity to do a round on the Immunology and Infectious Diseases ward. It was there that I first saw babies hospitalized for a disease known as severe combined immunodeficiency, or SCID. Seeing these children, whose illness had been barely mentioned during my medical training, was a seminal moment for me. These infants – who, because of a single gene defect that affected the development of their immune systems – were either overcome by infection or by the side effects of their treatment, and many had little chance of surviving past childhood. I understood then the devastation that rare genetic diseases can cause. As I looked after these children, I came to see even more fully that this suffering extended beyond the patient to the patient’s family. These early experiences in SCID had a profound effect on me, and my professional life since that time has been dedicated to improving outcomes for SCID and other rare genetic diseases through better diagnosis and better treatments. 

By the following year, 1993, I was involved in one of the first clinical studies ever undertaken of an ex vivo autologous hematopoietic stem cell gene therapy, and SCID was the first condition to be investigated. This gene therapy approach involved taking the child’s own blood stem cells (or hematopoietic stem cells – HSCs) and introducing a working copy of the missing or faulty gene before returning the gene-corrected cells back to the child. Over the subsequent years, our group and a few others worldwide made great strides in understanding the best vectors to deliver genes to blood stem cells, the ideal cell population to target, and the right preconditioning treatment for these patients.

As we saw the impact of HSC gene therapy in SCID and other immune and neurometabolic disorders, I came to realize that the huge potential of the therapies we were developing could not be fully realized if they remained solely in the academic environment. A future for gene therapy medicines would require commercial and manufacturing infrastructure, strategic planning, and investment if they were to be made as widely available as possible to patients. In 2015, I co-founded Orchard Therapeutics to bring this vision to life. 

The HSC Gene Therapy Approach

Through Orchard and through working with our academic partners, I believe we are at a very important stage for patients with rare diseases and their families. We’ve seen in numerous clinical studies that the approach of using a lentiviral vector to insert a functioning copy of a faulty gene into a patient’s extracted bone marrow cells has the potential to halt or reverse disease, and we’ve laid the groundwork of expanding the promise of HSC gene therapy into numerous other areas of unmet medical need.  

Today, Orchard and others are advancing HSC gene therapy for a series of different conditions. Driving this continued growth are, what I consider, the HSC gene therapy approach’s two main distinguishing potential benefits: a durable and potentially curative effect and the ability to deliver genes to the CNS through the natural ability of HSCs to cross the blood-brain barrier.

The durability of HSC gene therapy derives from the fact that these therapies use gene-corrected versions of a person’s own stem cells, which have an intrinsic ability to self-renew. In this process, not only do the HSCs self-renew, but they also divide and pass along the right genetic information to new cells, creating the potential for permanent disease correction following a single treatment.

The second benefit of this approach is the ability of gene-corrected HSCs to differentiate into multiple new cell types, including immune cells, red blood cells, macrophage and microglia, opening up the possibility to address multiple organ systems, including the brain. Distribution in the central nervous system has been notoriously challenging for gene therapies, and that has limited the range of diseases that have so far been successfully treated. However, recent data from our studies and others show that there are a population of gene-modified HSCs that can naturally cross the blood-brain barrier, distribute throughout the brain, engraft as microglia and express enzyme that is taken up by neurons.

Since our earliest days, HSC gene therapy has continued to primarily be explored as a treatment for very rare genetic diseases, where it has demonstrated curative potential.

More recently, based on our field’s deepening understanding of the genetic basis of various diseases, as well as the data emerging from Orchard and others’ clinical trials, researchers have begun to explore applications of various types of gene therapy in less-rare conditions. HSC gene therapy specifically holds great promise against otherwise intractable diseases, due to its advantages of potential durability and ability for gene-modified HSCs to differentiate into multiple new cell types and migrate and deliver genes into multiple different organ systems and tissues. I believe there’s a very exciting future ahead for the application of HSC gene therapy in a growing range of indications.

However, realizing that future will depend on both continued research and innovation, as well as strong commercial preparation and execution, to help these therapies progress from concepts in the lab to approved treatments for patients.

One component of this preparation will be improvements in diagnosis and disease education, especially of rare diseases. For the growing number of rare diseases that may become treatable with gene therapy in the future, rapid and accurate diagnosis will be an essential aspect of getting these treatments to the children who need them. And because some severe genetic diseases affecting children are rapidly progressing, diagnosis as early in life as possible is crucial to ensure these babies can access treatment within the window for it to be as potentially effective as possible. Therefore, comprehensive newborn screening is an essential companion to these emerging rare disease treatments.

Manufacturing capacity is another area that will need our sustained focus. At Orchard, we’re investing in innovative technologies to enable commercial scalability, such as transduction enhancers, stable producer cell lines and closed, automated processing of drug product. This will potentially reduce the amount of vector needed and drive efficiencies and quality enhancements over time.

Access to these therapies will also be key to address. Gene therapy providers, payers and hospitals are already beginning to think creatively within reimbursement and treatment models, but more innovation will be needed as more therapies come to market. One-time, potentially curative treatments are a radical departure from the chronic care model that much of our health care system was built around. If we are to realize the full potential of these therapies, we’ll need to collaborate to construct mechanisms to share data, track outcomes, and equitably spread risk across the health care ecosystem.

These challenges will take work, investment and risk to overcome, and there will be others along the way that we haven’t even identified yet. But I believe we as a society will rise to the challenge, for the same reason that compelled me to this field decades ago: There are children whose lives depend on our efforts, and it is our duty and our responsibility to bring these genetic medicines to them.