Delivery of Mitochondria Using Extracellular Vesicles as a Novel Therapy for ALS
Abstract
Ultimate applicability of the research: In ALS, the cells that control movement, motor neurons, break down and stop working. No matter the cause of ALS, familial or sporadic, one reason these cells stop working is that their power generators, the mitochondria, become damaged. Research over the past 3 decades has demonstrated this and yet clinical trials that try to repair the mitochondria have not been effective. This research will provide foundational results to advance a novel therapeutic approach: the delivery of new, healthy mitochondria to promote the health and function of the motor neurons. Mitochondria are the powerhouses of cells and produce most of the cell s energy to allow the cell to perform multiple complex functions. Mitochondria even regulate whether the cell lives or dies in diseases such as ALS. It is known that motor neurons contain damaged mitochondria during the very early stages of disease onset in ALS. The damaged mitochondria are known to cause multiple problems resulting in progression of the disease to a point of no return where the patient s cells cannot effectively respond to ALS drugs. Indeed, the current ALS drugs are only modestly effective at extending patient life span with the standard-of-care drugs allowing patients to survive for only as long as 3 to 6 months! Many different types of cells in the human body, including healthy neurons, naturally release tiny vesicles/buds, called microvesicles. A very interesting feature of the microvesicle is that they contain material such as healthy mitochondria. We are proposing to collect these mitochondria-containing vesicles from cell models of motor neurons to treat the experimental mouse model of ALS. The results from this study will establish the foundation to further advance microvesicles as promising therapy to decrease mitochondrial damage, increase motor neuron function, and therefore prolong survival of ALS patients. What type of ALS patients will microvesicles help, and how will this help them? Clinical studies in ALS patients have shown that mitochondrial abnormalities/damaged mitochondria are present both in the familial/genetic as well as the sporadic/non-genetic forms of ALS. Therefore, delivery of healthy mitochondria can be expected to decrease mitochondrial damage in all types of ALS patients -- regardless of how they acquire the disease. By decreasing the mitochondrial damage in the motor neurons that connect with the muscles, these microvesicles can promote healthy survival of the motor neurons and therefore allow normal functioning of the muscles connected to the now healthier neurons. Overall, this approach of delivering mitochondria using microvesicles will decrease muscle weakness and loss of muscle functions. What are the potential clinical applications, benefits, and risks of microvesicles? The most important advantage of delivering mitochondria using microvesicles lies in the fact that these microvesicles are very safe and will have minimal side effects/risks. Microvesicles are naturally derived from cells grown experimentally in a plastic dish, and ultimately may be derived from a sample from the individual patient, such as motor neurons derived from the patient s IPSCs collected from a skin sample. It is important to note that the project will determine that delivery of microvesicles containing mitochondria is safe AND effective in a limited motor neuron population in a mouse model of ALS. This is the critical first step for this development of this therapeutic idea. We are encouraged by our preliminary studies in a model of stroke that demonstrates effectiveness of this approach. From here, our future studies will determine the best route of delivery for an overall effect to delay disease progression and significantly extend survival. The projected time it may take to achieve a patient-related outcome and description of the interim outcomes. We will carry out the proposed studies in the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310218
Entities
People
- Devika Soundara Manickam
Organizations
- Duquesne University
- United States Army