Designer Platelets Reprogramming of Macrophages and Endothelial Cells: A Paradigm Shift in Cell-Based Therapy for Lung Disease
Abstract
Humans and most animals have platelets, tiny cells that travel in the blood stream. Although platelets are relatively simple cells, they have many functions that help their host; for example, they aid in clotting of blood to stop bleeding, and they work to fight infections. Platelets travel in the blood to every organ, where they interact with the cells lining blood vessels, as well as other cells. This characteristic of platelets raises the possibility that they could be modified to produce compounds they don’t normally make, but that could help treat or prevent a variety of diseases. That is, platelets could be modified to serve as tiny drug delivery vehicles. To make a platelet a drug delivery vehicle, one might remove platelets from the blood, induce them to take up RNA, which encodes the desired therapeutic protein, and then return them to the body, where they could travel to sites of disease to help fight the problem in new and novel ways. Such treatment could be thought of as creating “designer platelets,” which could be tailor-made to take specific therapeutic agents anywhere in the body. Generation of designer platelets has the potential to improve the ability of doctors to successfully treat a wide variety of diseases. By their nature, platelets come into close contact with endothelial cells, the cells lining blood vessels. In many diseases, endothelial cells become activated, which can lead to shock and other serious disorders. One example is acute lung injury, a term that is relatively general, but which refers to life-threatening lung inflammation that can be brought on by a wide variety of insults. These insults include infection by bacteria or viruses, trauma, inhalation of toxic substances, or even surgery or blood transfusions. Acute lung injury can at times progress to acute respiratory distress syndrome (ARDS), the most severe form of lung injury. More than 40% of people who develop ARDS die in spite of intensive therapy. The high rate of death in people that develop ARDS indicates that more effective therapies are needed. It is possible that designer platelets can take healing molecules to the endothelium of the blood vessels in the lung, preventing or mitigating acute lung injury and ARDS. However, before designer platelets can be created, we need to understand exactly how to get platelets to make therapeutic proteins; this activity is likely critically influenced by experimental conditions such as time and temperature of incubation and characteristics of the RNA the platelets must use to make a given therapeutic protein. Although we have already been able to get platelets to accept RNA and produce proteins that they do not normally produce, in this research we will determine the optimal conditions for inducing designer platelets to take up RNA and to produce the protein encoded by the RNA. After this, we will test the function of designer platelets in acutely inflamed lung, using a model of acute lung injury that is due to exposure to a dietary toxin, in cattle. We will demonstrate the presence of designer platelets producing a protein they don’t normally make in a site of serious inflammation in the lung. Once we have completed our objective to determine the precise biological conditions under which platelets take up and produce protein in an effective and regulated manner from RNA we give them and once we confirm the conditions that allow control of protein delivery, we will have set the stage for new clinical research using platelets as vehicles to efficiently deliver specific treatments for a variety of diseases. This proposal addresses the topic area of acute lung injury, but the work will likely be applicable to many kinds of diseases in many organ systems.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810771
Entities
People
- Camilo Bulla
Organizations
- Mississippi State University
- United States Army