"Our ex vivo lentiviral gene therapies are designed to drive durable production of the functional protein throughout the patient’s body, thereby potentially addressing symptoms from ‘head to toe.’”

What are the indications that we are entering into a golden age for gene therapy and what hurdles must the industry overcome to become mainstream?

While there have been just a handful of gene therapies approved, I believe that we’re entering a new era for this important modality. Within a decade or so, I believe that we have the potential to transform the lives of many people living with serious genetic disorders. We hope to untether them from a lifetime of chronic treatments and deliver a functional cure with a single dose of a gene therapy.

One key challenge is matching genetic diseases with the right delivery system. There are two primary ways to deliver therapeutic genes – AAV vectors, which are typically used to insert the therapeutic gene into patients’ cells “in vivo” or inside their bodies, and lentiviral vectors, which are typically used to integrate the therapeutic gene into the patients’ chromosomes “ex vivo,” or outside their bodies.

AAV vectors are well-suited for diseases that affect one compartment or cell type in the body, but they are not as effective as lentiviral vectors for diseases that affect the whole body. We work exclusively with ex vivo lentiviral gene therapies for lysosomal disorders, which are designed to have a unique ability to deliver therapeutic protein from head to toe – potentially including the brain and the spinal cord as well as peripheral tissues.

Another important challenge for gene therapies is that of scale. It’s not easy to manufacture cell and gene therapies, and it’s even tougher to manufacture them at commercial scale. So, it’s critical that companies develop sound processes, secure their supply chains and build manufacturing systems that will enable them to reach a broad market once they have secured regulatory approval.

How does AVROBIO’s plato platform help with scalability?

plato® is our proprietary platform designed to optimize the safety, potency and durability of our gene therapies while potentially enabling rapid scale-up and commercialization. Each of our product candidates uses a four-plasmid vector system. Three of the four plasmids used in every vector are the same; one plasmid is unique to the disease indication. The beauty of plato is that as you move from one indication to another, you simply change out one plasmid.

Another key to plato is automated manufacturing of the drug product itself.

What effect do lysosomal disorders have on patients and how is AVROBIO attempting to redefine the current standard of care?

Lysosomal disorders are caused by a mutation in a single gene responsible for making a specific enzyme or protein needed for proper functioning of the lysosome, important structures within cells that recycle cellular materials. When lysosomes don’t function properly, toxic materials build up and cause debilitating symptoms throughout the body, typically including the heart, kidney, liver and/or bones. About half of lysosomal disorders also affect the central nervous system. Lysosomal disorders are chronic and progressive, with symptoms worsening over time and the potential for a significantly shortened life span.

The standard of care for many lysosomal disorders is enzyme replacement therapy (ERT), which replaces the enzyme needed for healthy cellular function, but it does not halt the overall progression of disease and it cannot address symptoms in the central nervous system.

AVROBIO is dedicated to transforming the standard of care for lysosomal disorders by tackling the root cause of these genetic diseases. Our ex vivo lentiviral gene therapies are designed to drive durable production of the functional protein throughout the patient’s body, thereby potentially addressing symptoms from “head to toe.” We start with the patient’s own hematopoietic stem cells, use a lentiviral vector to transduce them in the lab to insert a therapeutic gene, and then re-infuse them into the patient, where they can engraft in the bone marrow. Following engraftment, these cells are expected to produce generations of daughter cells, each carrying a copy or several copies of the therapeutic gene. The patient should have trillions of genetically corrected cells in circulation, each expressing the therapeutic enzyme needed to keep the lysosomes functioning properly. Through this approach, we hope to bathe all tissues and cells in the necessary enzyme 24/7.

Importantly, our lentiviral approach is designed to enable treated cells to cross the blood-brain barrier and engraft in the brain and central nervous system. This head-to-toe reach – which is unique to ex vivo lentiviral gene therapy – allows our therapies to potentially address the cognitive symptoms that are so important with many lysosomal disorders, as well as to prevent organ failure and other systemic complications.