Innovative SDF-1 mRNA delivery to reverse diabetic neurovascular erectile dysfunction
Johanna Hannan   (Greenville, NC)
Diabetes mellitus (DM) is a chronic disease that impacts over 422 million people worldwide of which more than 90% of all diagnosed cases are type 2 DM (T2DM). Uncontrolled DM leads to vascular dysfunction, neuropathy, and erectile dysfunction (ED). ED is a highly prevalent, chronic health challenge with profound negative impacts on their quality of life and well-being. Oral formulations of phosphodiesterase type 5 (PDE5) inhibitors have provided a breakthrough in managing ED but are frequently ineffective in diabetic men due to underlying neurovascular dysfunction. A therapeutic modality that can prevent the pathophysiology of the disease, while providing a long-lasting therapeutic benefit is sorely needed. We have recently discovered that human recombinant stromal cell-derived factor-1 (SDF-1) promotes regeneration of penile vasculatures, nerves, and muscles to restore erectile function in a rat model of ED. The improvement was associated with increases in major pelvic ganglion neurons and growth factor expression, upregulation of stem-cell associated genes and decrease in penile fibrosis. We propose to develop mRNA-based SDF-1 therapy, with a particular focus on using nanoparticle-based platforms providing safety and efficient mRNA delivery to penile cells, for sustainable ED treatment. We will use environmentally-sensitive cationic polymers that gradually degrade in physiological environments to facilitate mRNA release and removal of carrier materials from body. This proposal will assess the efficacy of two custom-synthesized nanoparticle candidates to package and deliver SDF-1-encoding mRNA into the injured penile tissues of a rat model of diabetic ED. We will determine the optimal dose with a dose escalation study in healthy rats (Aim 1). Once the doses have been selected, we will determine if they are able to recover erectile function in a rat model of T2DM, the Zucker Diabetic Fatty obese rat (Aim 2). A multidisciplinary team science approach has been used in this proposal. Successful execution of the proposed studies would pave the way for clinical development of novel mRNA-based therapy for treating patients with diabetic ED, particularly those poorly responsive to current standard-of-care treatments.
Data for this report has not yet been released.