Microglia-Targeted MRI-PET Traceable Nanovectors: Theranostic Platform for Tracking and Shaping Microglia Reactivity to Improve ALS Therapy
Abstract
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig s disease, is a progressive neurodegenerative disorder that targets motor neurons (nerve cells responsible for voluntary muscle movement) in brain and spinal cord. ALS affects 1 to 3 per 100,000 individuals annually and results in paralysis and fatality from respiratory failure. Approximately 5,000 Americans are diagnosed with ALS each year, with only one-fifth of patients living for 5 years or more after diagnosis. While 90% of cases have no family history (sporadic ALS), the rest (10%) of cases are familial ALS. Despite several studies carried out over the past 20 years and a number of potential drugs tested in randomized controlled trials, ALS still lacks effective treatments. Riluzole remains the only Food and Drug Administration-approved treatment for the disease, although it extends life by only a few months. Therefore, the discovery of novel therapeutic strategies is needed. Neuroinflammation, characterized by activation of glial cells (namely astrocytes, oligodendrocytes, and microglia) at sites of neuronal degeneration, is a pathological hallmark shared by sporadic as well as familial ALS. Interestingly, preclinical data point to restoration of microglial neuro-supportive functions as a therapeutic strategy with potential profound impact on the disease progression. Thus, finding efficient approaches capable of tuning microglia reactivity to favor a pro-regenerative phenotype has become an area of intense investigation. Our project will optimize and validate a novel pharmacological tool based on small drug carriers, called nanoparticles (NPs), composed of biocompatible polymeric materials with dimensions in the nanometers scale. These NPs are specifically tailored to obtain controlled and selective multiple-drug release only in activated microglia. The specificity for the cellular target is provided by conjugating the NPs to selective positron emission tomography (PET) tracers already validated at preclinical and clinical level for identification of activated microglia cells in brain and spinal cord regions characterized by prominent neuroinflammation and neuronal demise. The major strength of this strategy is that the NPs can be functionalized to become traceable through non-invasive molecular imaging approaches (i.e., magnetic resonance imaging [MRI] and PET); this gives the possibility to track the drug biodistribution and identify the compromised neuronal districts in vivo. Through this strategy, we expect to improve the efficacy and reduce side effects of potentially therapeutic compounds and to gain a higher chance to effectively modify disease progression for both sporadic and familial ALS by manipulating the microglia behavior in vivo. We believe that dampening specifically the release of reactive oxygen species or inflammatory cytokines while increasing the release of neurotrophic factors by microglia at sites of neuronal demise may contribute to shape a pro-regenerative motor neuronal microenvironment. In particular, here we will validate NPs loaded with molecules targeted to well-known molecular pathways involved in ALS pathology, i.e., diapocynin (an inhibitor of the pro-oxidant molecule NADPH-oxidase type 2) and anti-sense oligo-deoxynucleotides acting as inhibitors of miR-155, which has been recently identified as a master regulator involved in aberrant cytotoxic microglia functions in patients as well as ALS rodent models. Altogether, this approach will provide a proof-of-concept that the nanoparticle platform validated in this project may be used for improved therapeutics efficacy in ALS, possibly speeding up the clinical translation of promising compounds to ALS patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710036
Entities
People
- Marco Peviani
Organizations
- Dana–Farber Cancer Institute
- United States Army