Can EVs Expand the Therapeutic Effect of Gene Replacement for Tsc1 in Brain?
Abstract
These studies are designed to increase the effectiveness of gene therapy in a TSC1 mouse model. This model focuses on brain lesions that underlie neurologic symptoms in TSC1 patients. These lesions, which are mimicked in our mouse model, include overgrowth of the cells lining the ventricles, which leads to hydrocephalus in patients, and increased size, signaling, and proliferation of brain cells, which may contribute to epilepsy. Current therapies for hydrocephalus and, to some extent seizures, rely on neurosurgery and treatment with analogues of the drug rapamycin. Neurosurgery is invasive and can lead to complications, and drug treatment has to be continuous and is associated with compromise of the immune system and potentially interferes with brain development in children. This defines an unmet medical need. We envision our therapy, which involves gene replacement therapy using adeno-associated virus vectors, which are now used for treatment of several neurologic diseases in patients, can be expanded by engaging membrane vesicles released by cells throughout the body to carry the therapeutic cargo over a broader biodistribution, not only in the brain but in other tissues. In clinical practice, gene therapy using these vectors is carried out once by injection into the bloodstream with the vector spreading throughout the body, including across the blood-brain barrier. Replacement therapy lasts for many years without further treatment. This approach could be used in children or adults to prevent new lesions and decrease the size of existing lesions. This therapy has the potential to prevent hydrocephalus and decrease epilepsy in children and to reduce size of lesions in peripheral overgrowths, such as renal angiomyolipoma and lymphangioleiomyomatosis (LAM), although a much larger dose of vector would be needed in adults as compared to children if given through the bloodstream. Although these viral vectors are used clinically in all ages, they may run the risk of being taken up mostly by liver cells with the possibility of toxic effects there. Also, the modifications to the replacement protein, hamartin, to increase its transfer by membrane vesicles among cells, may elicit a negative immune response. This will be monitored carefully in our animal model. Abnormally high expression of the replacement protein may elicit some toxicity, which will be evident in our mouse model, but to date has not been a problem. Our gene replacement therapy using these virus vectors may reach clinical trial within 2 years. Adding in the modification of the hamartin protein to increase its biodistribution in the brain and other organs would take another 2 years to accumulate data for the U.S. Food and Drug Administration (FDA) to review prior to clinical trials. Based on the amazingly positive response in our mouse model of TSC1 to vector-mediated gene replacement therapy – extending lifespan from 50 days to over 200 days, and the extensive expertise of our laboratory in using membrane vesicles in the body to expand the range of gene replacement, we anticipate that this combined approach can be paradigm shifting and improve symptoms in organs throughout the body of TSC1 patients. Our initial focus is on the brain as that is our area of expertise, and we will make our results available to the scientific community, share all vectors, and seek collaborations with investigators focused on the brain and other organs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310338
Entities
People
- Xandra O. Breakefield
Organizations
- Massachusetts General Hospital
- United States Army