Programming Smart Commensal Bacterium to Monitor and Ameliorate Mitochondrial Dysfunction
Abstract
Topic Area: This proposal targets mitochondrial disease, which is one of the topic areas of the Fiscal Year 2020 Peer Reviewed Medical Research Program (PRMRP). The Critical Problem to Be Addressed: Patients suffering from mitochondrial diseases display multi-organ disorders, which cause clinical conditions that pertain to other topic areas of 2020 PRMRP. For example, mitochondrial mutations also occur in patients with congenital heart defects. In mitochondrial diseases, mutations in certain mitochondrial genes can cause the inefficiency of our body to produce energy. For instance, Leigh syndrome, caused by mitochondrial gene mutations, is characterized by elevated levels of NADH, a reducing molecule inside cells. Moreover, a substance called lactate can build up in the body that causes the feeling of muscle soreness, and excessive lactate is often found in the blood, urine, or the fluid that surrounds the brain and spinal cord of people with Leigh syndrome. As a result, the serum lactate concentration has been used as one of biomarkers for the proper functioning of mitochondria. Recently it was demonstrated by others that irreversible conversion of serum lactate to pyruvate via systemic delivery of bacterial enzymes, named LOX and CAT, could result in the rapid entry of circulating pyruvate back to host cells, which subsequently help alleviates certain mitochondrial problems. This finding suggests a new way of correcting mitochondrial dysfunction by targeting circulating lactate. However, systemic delivery of bacterial enzymes in our body to treat mitochondrial diseases can be problematic primarily due to (1) potential induction of immune responses, (2) lack of precise dosage control, and (3) requirement for frequent administration. The Innovation of the Idea: Inspired by a recent study in which certain gut bacteria were found to metabolize blood-derived lactate in the gut, the central objective of this proposal is to engineer an indigenous gut strain, named Bacteroides thetaiotaomicron (BT), to synthesize and deliver LOX and CAT enzymes as therapeutics in the gut, which convert serum lactate to pyruvate. BT is prevalent and abundant in humans, and using BT to administer therapeutics in the gut can potentially provide a long-lasting pill against the disease. Importantly, instead of constantly producing the enzymes in the body that may cause side effects, we will engineer a negative feedback system in BT to enable drug delivery in a sense-and-respond manner. Specifically, when the serum lactate is elevated above the cut-off value for mitochondrial disease, the bacteria will be able to sense the disease since lactate has been used as one of biomarkers for mitochondrial dysfunction. Furthermore, they will react to convert lactate to pyruvate by producing LOX and CAT at a level proportional to the serum lactate concentration. However, the negative feedback circuit will lower or turn off the administration of therapeutic enzymes when lactate drops below the cut-off lactate level for mitochondrial diseases. Altogether, this strategy will regulate the timing and dosage of therapeutic enzymes in a smart and safe manner. The Ultimate Applicability and Impact of the Research: Knowledge generated from this research will become the foundation for future work in a mouse model of Leigh syndrome to comprehensively assess the therapeutic efficacy of our engineered gut bacteria. Moreover, the proposed study will lay the foundation for future clinical studies to offer an innovative therapeutic approach to benefit a diverse population of patients affected by mitochondrial diseases including military Service members, veterans, and their family members.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110016
Entities
People
- Jiahe Li
Organizations
- Northeastern University
- United States Army