SDF-1 mRNA gene therapy for restoration of erectile function

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Abstract Erectile dysfunction (ED) affects about 18 million men in the U.S. and is estimated to affect 322 million men worldwide by 2025. ED can have a profound negative impact on quality of life and well-being and is often associated with anxiety and depression. ED also represents a significant economic burden, with over $4 billion spent in 2017 in the U.S. ED is a common consequence of diseases that affect the microvasculature and nervous tissue, including common chronic diseases such as hypertension, dyslipidemia, and diabetes, and a frequent side effect of prostate cancer treatment. Currently available ED treatments are moderately effective at best, have high discontinuation rates, and address only the symptoms, not the underlying causes. To address the need for novel treatments for ED, Evincis Bio is developing a regenerative gene therapy based on stromal cell‐derived factor‐1 (SDF-1) mRNA. SDF-1 is a highly conserved chemokine that regulates an endogenous repair pathway used by many tissues throughout the body, such as the heart, brain, muscle, and vasculature. Often upregulated following injury, SDF-1 signaling leads to stem cell migration to the injury site. SDF-1 binds to its receptor CXCR4 on resident tissues, including nerves, muscle, and vasculature, inducing angiogenesis, neurogenesis, anti-apoptotic pathways, and upregulating the expression of growth factors. Evincis has demonstrated that SDF-1 penile injections improve erectile function in a rat model of ED. This improvement was associated with increased major pelvic ganglion (MPG) neurons, decreased penile fibrosis, and increased growth factor expression in penile tissues. SDF-1 penile injections were shown to upregulate the expression of stem cell-associated genes in the MPG and erectile tissue. Evincis has also demonstrated the feasibility of targeted mRNA-based gene expression in penile tissues. In fact, mRNA technology is being utilized by several current COVID-19 vaccines. In this Phase I project, Evincis will conduct in vitro and in vivo dosing, efficacy, and safety studies to support further clinical research. This will be accomplished through the following specific aims: 1) Screen engineered mRNA candidates in vitro for expression efficiency and cytotoxicity; 2) Determine EVI-200 dosage, expression duration, and safety in vivo; and 3) Perform efficacy and cancer safety studies in vivo. These studies will support further Phase II work, in which Evincis will expand the preclinical testing to additional disease states, investigate different nucleic acid carriers, perform pharmacokinetic and toxicology studies, and initiate the GMP setup necessary to support an IND application and start a Phase I clinical trial. Evincis will pursue approval as a biologic, resulting in a product J-code and stand-alone reimbursement for the in-office procedure. If successful, EVI-200 will be the first therapy specifically designed to treat the underlying causes of ED due to injury of nerve, muscle, and vascular tissue, and potentially provide a cure for millions of individuals. This project will also serve as a proof-of-concept for EVI-200 as an mRNA- based regenerative therapy for other conditions, such as urinary incontinence.