In Vivo Delivery of Precise Gene Correction for Treatment of Fanconi Anemia
Abstract
Background: Fanconi anemia (FA) is the most common type of inherited bone marrow failure (BMF). Blood problems start at an average of 8-10 years of age in reported cases. This devastating disease has greater than 50% mortality by age 20. We know what changes to DNA cause FA, but there is no current way to reverse them. To overcome this problem, we will combine two exciting new technologies. (1) Prime Editing, which can write new DNA sequences in human cells. (2) BacMam, a safe type of virus already applied in biotechnology, but adapted for medical use. Hypothesis: Restoration of normal blood production in FA is possible by combined action of BacMam and Prime Editing in bone marrow. The critical problem or question to be addressed by the proposed research project: Restoration of normal bone marrow allows FA patients to live a normal life to adulthood. Currently, this is achieved by bone marrow transplant. Doctors need to find a compatible bone marrow donor, yet in 30% of Fanconi patients this is not possible. For the remaining 70%, the transplant is expensive and can have severe side effects. These side effects can cause death. A different type of treatment is to use the patient’s own cells. Their cells are manipulated outside the body to correct the disease-causing gene mutations. They are then re-injected. This process removes the need for a donor and reduces potential side effects. But this approach is also expensive, and only an option for a few patients at very few locations. In our project, using a new mouse model of FA, we will determine if it is possible to repair the patient cells without removing them from the body. We will give a simple injection or transfusion of the BacMam-Prime Editor tool. We will then use various methods to show that normal bone marrow function can be restored. This approach could benefit most patients and be delivered at almost any location with basic medical facilities. The Fiscal Year 2021 Bone Marrow Failure Research Program Idea Development Award Focus Area the Work Seeks to Address Is: Find effective BMF treatments and cures. Innovative Aspects of the Proposed Research: We are using two cutting edge technologies: Prime Editing (discovered in 2019) and BacMam (first used in patients in 2017). We are the first team to combine these two technologies and apply them to use in bone marrow. A major aim of our project is to also describe a world-first mouse with FA symptoms (called FancL*). Unlike previous mouse models, FancL* can be used to test any new treatment that relies on fixing errors in DNA found in human patients. BacMam-Prime Editors are the first, highly innovative approach to be tested in these mice. Demonstration of success in mice will allow us to rapidly advance these technologies into humans through our close network of treating physicians. Impact on the Field of BMF Research in the Short and Long Term: A direct injection system of gene editing in FA will: 1. Reduce dependence on transplantation from relatives and unrelated donors, which has a high cost, high incidence of side-effects, and relatively high death rate. 2. Ease decision making for parents/carers/doctors: The upfront risk of recipient death leads to both doctors and patients/parents delaying transplantations. As our approach could be done prior to onset of BMF, it is predicted to lead to improved patient outcomes. Less risk means easier choice to proceed very early after diagnosis. 3. Extend capacity in these cutting-edge gene editing technologies to BMF syndromes 4. Adapt to most mutations (76% of FA patients have at least one editable allele. Source: Fanconi Anemia Research Fund). 5. Be easily transferred to other BMF syndromes such as Diamond-Blackfan Anemia, Shwachman-Diamond syndrome, and telomere biology disorders. 6. Be safer than other types of DNA manipulation technologies. 7. Transform the treatment of BMF from a cell-based therapy (i.e., e
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210541
Entities
People
- Andrew Deans
Organizations
- United States Army