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.
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:
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.
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:
AVROBIO
