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Where we stand: A perspective on AVROBIO’s place in the gene therapy landscape

Former President & CEO

Geoff MacKay | Former President & CEO

Last month, AVROBIO presented an update at the American Society of Gene and Cell Therapy annual meeting that we believe illustrates the broad range of potential benefits that comes with using patients’ own hematopoietic stem cells (HSC) to address genetic disease. Early data from our collaborator-sponsored Phase 1/2 clinical trial in cystinosis showed consistent expression of the therapeutic gene in all five patients treated to date and improvements across a number of clinical measures, including blood, eyes, skin and gastrointestinal mucosa. And for the first time, researchers shared early data showing stabilization, and in some cases improvement, across several neurocognitive measures in two patients. Similarly, preclinical research in a mouse model of Pompe disease showed a clean tolerability profile and durable expression of the therapeutic gene, and significantly reduced toxic accumulation of glycogen , including in the cardiac and skeletal muscle as well as the central nervous system (CNS).

This work is incredibly important as a foundation for our ongoing clinical programs in lysosomal disorders, where the systemic and cognitive effects of these diseases often are not addressed adequately by the current standard of care. For example, enzyme replacement therapy (ERT) can slow the progression of disease, but it cannot cross the blood-brain barrier to arrest the declines in common CNS manifestations such as visual motor integration, motor coordination and visual perception that are often observed in people with cystinosis.

AVROBIO was founded in 2015 with the goal to harness the curative potential of genetic modification with the regenerative benefits of HSCs, leveraging HSCs’ natural properties that potentially can pass genetic modifications on to their cellular progeny and distribute them throughout the body, from head to toe. HSCs are found in the bone marrow, where they differentiate to produce every kind of blood cell – macrophages, T cells, B cells, erythrocytes (aka red blood cells) and many others.

In fact, although AVROBIO has traditionally referred to itself as a lentiviral gene therapy company, we might be more fairly characterized as an HSC company. Although we of course use next-generation lentiviral vectors to genetically modify HSCs, the vectors themselves never enter the patient’s body. It is the patient’s own cells, augmented with a missing gene intended to produce a necessary protein, that constitute our drug product.

The power of HSCs

Their primordial role gives HSCs multiple properties that make them well-suited to address genetic disease at its root. First, they can be removed from the body, modified and re-infused. In fact, donor bone marrow transplants have been conducted for more than 60 years in over 1.5 million patients worldwide.[i] Second, because HSCs are precursor cells that give rise to all blood cells, their progeny have access to every tissue in the body, including the brain and spinal cord. And finally, the presence of a stable HSC population in the bone marrow means that any genetic modification should continue to be passed on to daughter cells, potentially for the lifetime of the patient.

Today, more than 400 people have received some type of gene therapy designed to genetically modify their HSCs. One recent study[ii] found that in clinical trials using lentiviral vectors to insert the modified genes into the HSC genome, engraftment rates have been 99%. And because the HSCs are a patient’s own, they do not pose the risk of provoking an immune response, which may have caused potential safety issues in some other types of gene therapy.

Broad applications

These properties make genetically modified HSCs potentially well-suited across a broad spectrum of genetic diseases where there is urgent unmet medical need. They are obvious candidates for the treatment of genetic diseases that directly affect HSC daughter cells, such as sickle cell disease (SCD) and beta thalassemia. In these conditions, mutations in a gene encoding part of the hemoglobin protein affect the function of red blood cells. Investigational HSC gene therapies currently in development have the potential to free people with these conditions from a regimen of frequent blood transfusions and drugs that often come with substantial side effects, along with the potential to live with less pain and pursue more physical activities. One HSC gene therapy for beta thalassemia and one for SCD have been approved for use in Europe and are currently under consideration by the U.S. Food and Drug Administration.

More rare, but similarly promising as a potential application for HSCs, are the primary immunodeficiency disorders (PIDs), which result from a wide variety of mutations affecting different components of the immune system.[iii] Children born with these conditions can be particularly susceptible to infections, sometimes requiring extreme protective measures such as isolation in sealed chambers with controlled air flow. Because HSCs give rise to every type of blood cell affected by this family of disorders, these gene therapies have the potential to address a wide variety of PIDs at their root, and children have been successfully treated using this approach since the 1990s.

The third major area in which HSCs potentially offer a major advantage is in the treatment of metabolic diseases. While HSC-based treatments for hemoglobinopathies and PIDs aim to make repairs to cells that ultimately derive from hematopoietic progenitors in the bone marrow, this technology can also be used to treat inherited deficiencies in other cells. In these cases, correct copies of affected genes are engineered into HSCs so that their descendants produce a working copy of a protein that is otherwise flawed or missing across all of a person’s cell populations. One gene therapy for the rare metabolic disease metachromatic leukodystropy has been approved for use in Europe.

At AVROBIO, we concentrate on a family of inherited metabolic diseases called lysosomal disorders. Lysosomal disorders are a family of genetic conditions, each caused by changes in a particular gene involved in helping subcellular organelles called lysosomes recycle molecular materials. When one of these genes does not function properly, molecular waste products build up to toxic levels inside cells. Depending on the type of material and the rate of accumulation, lysosomal disorders can impact different organs at various degrees of severity.

The current state of care for lysosomal disorders involves regular infusions of enzymes needed to prevent the buildup of cellular waste. For example, people with Gaucher disease receive glucocerebrosidase, while those with Pompe disease get alpha-glucosidase. In cystinosis, the strategy is slightly different, employing regular doses of a compound called cysteamine that breaks down accumulated waste material. All of these treatments have limitations, however. And as I mentioned at the outset of this article, current treatments cannot cross the blood-brain barrier to prevent disease progression in the neurons and other cells of the CNS.

Potential durability of head-to-toe reach

A number of different gene therapies have been proposed, and some have been tried, as a way to overcome the limitations of currently available treatments. But some gene therapy approaches do not reliably reach the brain, which can be severely affected in these disorders and may be overlooked as a site of disease progression in others. In addition, the effectiveness of some gene therapies can diminish over time as treated cells die off without passing on their modified genes, which also makes them poorly suited for pediatric use.

We believe HSCs have neither of those drawbacks. Once resident in the bone marrow, HSCs are designed to be a bottomless well of corrected genetic material. And because HSCs give rise to cells that can circulate everywhere in the body they are expected to cross the blood-brain barrier, creating the potential to extend to every tissue, head to toe.

With HSCs at the core of our technology, we believe that durability and full-body reach potentially can be achieved across a broad spectrum of lysosomal disorders and patient populations. A recent review of gene therapies using HSCs published in Molecular Therapy surveyed clinical progress in the field over the past two decades and concluded that “substantial disease correction was observed in most treated patients.”[iii]

Where does AVROBIO stand? I believe our long-standing application of HSCs puts us at the forefront of an extremely promising and growing sector in cell and gene therapy. This sector includes a growing number of companies that are working to enhance the curative potential of genetic modification with the regenerative potential of HSCs to make sufficient, sustained and, if needed, supraphysiological levels of functional protein, building on industry-wide clinical data that have demonstrated the durability, reach and adaptability of HSCs in a broad spectrum of indications, with the ongoing promise to impact the lives of patients. And that is a pretty exciting place to be.


[i] Granot, N. and R. Storb. History of hematopoietic cell transplantation: history and progress. Haematologica. 2020; 105 (12) 2716-2729.

[ii] Tucci, F. et al. A systematic review and meta-analysis of gene therapy with hematopoietic stem and progenitor cells for monogenic disorders. Nature Communications. 2022; 13: 1315.

[iii] Tucci, F. et al. Update on clinical ex vivo hematopoietic stem cell gene therapy for inherited monogenic diseases. Molecular Therapy. 2021; 29(2): 489-504.