Transformation of CD4+ T cell effector to regulatory (Teff to Treg) cells have been shown to attenuate
disease progression by restoring immunological balance during the onset and progression of
neurodegenerative diseases. In our prior studies, we defined a safe and effective pathway to restore this balance by restoring Treg numbers and function through the daily administration of the
cytokine granulocyte-macrophage colony-stimulating factor (
GM-CSF). These studies were conducted as a proof-of-concept testing in
Parkinson's disease (PD) preclinical models and early phase I clinical investigations. In both instances, they served to ameliorate disease associated signs and symptoms. However, despite the recorded efficacy, the
cytokine's short half-life, low bioavailability, and
injection site reactions proved to be limitations for any broader use. To overcome these limitations,
mRNA lipid nanoparticles encoding an extended half-life
albumin-
GM-CSF fusion
protein were developed for both mouse (Msa-
GM-CSF) and rat (Rsa-
GM-CSF). These formulations were tested for immunomodulatory and neuroprotective efficacy using
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (
MPTP) and human wild-type
alpha-synuclein (αSyn) overexpression preclinical models of PD. A single dose of the extended half-life mouse and rat
mRNA lipid nanoparticles generated measurable
GM-CSF plasma
cytokine levels up to four days. Increased Treg frequency and function were associated with a resting microglial phenotype, nigrostriatal neuroprotection, and restoration of brain tissue immune homeostasis. These findings were substantively beyond the recorded efficacy of daily recombinant wild-type
GM-CSF with a recorded half-life of six hours. Mechanistic evaluation of neuropathological transcriptional profiles performed in the disease-affected nigral brain region demonstrated an upregulation of neuroprotective CREB and synaptogenesis signaling and neurovascular coupling pathways. These findings highlight the
mRNA-encoded
albumin GM-CSF fusion
protein modification linked to improvements in therapeutic efficacy. The improvements achieved were associated with the medicine's increased bioavailability. Taken together, the data demonstrate that
mRNA LNP encoding the extended half-life
albumin-
GM-CSF fusion
protein can serve as a benchmark for PD immune-based
therapeutics. This is especially notable for improving adherence of drug regimens in a disease-affected patient population with known
tremors and gait abnormalities.