Our ApproachTreating the Whole Body

ONE therapeutic gene: distributed head-to-toe

Our investigational gene therapies are being studied to assess their impact on every tissue in the body, including the brain and spinal cord.

Our gene therapies are investigational and have not been approved by FDA or any other regulatory agency. Their safety and efficacy are being studied in clinical trials.

Why is it important to treat the whole body?

Many genetic disorders, especially lysosomal disorders, have a wide variety of potential symptoms that manifest simultaneously throughout the patient’s body. For a therapy to potentially halt, prevent or reverse these symptoms, it must integrate into cells that distribute throughout the body, “head-to-toe.”

Our investigational gene therapies are intended to cross the blood-brain barrier and therefore address the central nervous system (CNS) symptoms that are an important component of disease for many people living with lysosomal disorders. For more information on how lysosomal diseases affect the body, please see our resources on Gaucher disease, Hunter syndrome and Pompe disease.

How we treat the whole body

Our investigational therapies start with the patient’s own hematopoietic stem cells. They are genetically modified in a manufacturing facility by inserting a lentiviral vector containing a therapeutic gene. The genetically modified stem cells are then infused back into the patient. The key to successful head-to-toe treatment is to ensure that the genetically modified cells settle in, or engraft, in both the bone marrow and CNS. Engraftment supports the goal of delivering throughout the body either functionally corrected cells and/or cells that act like mini factories producing therapeutic protein.

How does that happen, exactly? Dive in for a closer look:

To prepare the central nervous system and bone marrow to receive and support genetically modified cells, the patient undergoes a personalized conditioning regimen. The use of a targeted dose of an established conditioning agent, busulfan, is being investigated in some lentiviral gene therapy clinical trials.
The genetically modified stem cells are then infused and travel to the bone marrow, where some will engraft and differentiate into a wide variety of immune and blood cells.

Did you know?
The bone marrow is the biggest producer of new cells that travel around the body – trillions of potential "living factories" for the therapeutic protein.
The potential to differentiate into multiple, specialized cell types with different functional implications is a unique aspect of stem cells and makes them particularly powerful agents in delivering therapeutic genes. Each of the daughter cells that arise from our genetically modified stem cells is expected to carry a copy or a few copies of the therapeutic gene required to produce the functional protein needed for healthy cellular function.

Did you know?
Among the daughter cells are macrophages, which can either be fixed (meaning they remain in one tissue type) or free (meaning they travel throughout the body, often gravitating toward injured tissue). Both types express therapeutic protein and thus can potentially help prevent, halt or reverse damage.
Trillions of nucleated daughter cells are designed to produce the functional protein and distribute it to tissues from heart to muscle to bone as they travel on their normal circuit throughout the body.
One kind of nuceleated daughter cell, the monocyte, crosses the blood-brain barrier to enter the brain and spinal cord, where they become microglia. Here, researchers are investigating how microglia may produce a functional protein and distribute it to the brain and spinal cord.
Why conditioning matters

Prior to treatment with investigational lentiviral gene therapies, patients receive a conditioning medication to clear space in the patient’s bone marrow, which is intended to allow the genetically modified cells to permanently engraft in bone marrow, brain and spinal cord, produce generations of daughter cells carrying the therapeutic gene and make the functional protein the patient needs to maintain health.

Precision dosing with busulfan

AVROBIO uses a well-established conditioning medicine called busulfan, which enables engraftment and ultimately helps enable durable distribution of therapeutic protein throughout the body. Unlike other conditioning agents, busulfan crosses the blood-brain barrier and is critical to addressing diseases involving the CNS.

Similar to how keyhole surgery revolutionized surgery, we believe Target Concentration Intervention (TCI) has evolved the use of busulfan for gene therapy.

AVROBIO’s approach with TCI is designed to enable personalized conditioning deploying state-of-the-art precision dosing. Targeting is intended to reduce side effects while maximizing genetically modified stem cells engraftment in the bone marrow.

The conditioning process is associated with known side effects and does have risks. For instance, patients are more vulnerable to infection and bleeding for several weeks after conditioning. They may experience transient side effects such as fatigue, nausea, hair loss and mouth sores. Some of these side effects can be managed proactively with supportive care. There may be long-term risks to fertility; individuals undergoing conditioning may be advised to freeze their eggs or sperm in advance of the treatment.

To learn more about Bu90-TCI, check out these resources:


Explore more

Our Approach

Learn more about our personalized approach to gene therapy.

Lysosomal Disorders

Understand the facts about lysosomal disorders.

Patient Advocacy

Connect with our patient advocacy and engagement team.