Preclinical Evaluation of UDCA-Containing Oral Formulation in Mice for the Treatment of Wet Age-Related Macular Degeneration

Abstract

As a posterior ocular disease, wet age-related macular degeneration (WAMD) has been known to be related to vision loss, accompanying ocular complications. The intravitreous injection of VEGF antibodies has been reported to be an effective treatment to relieve symptoms of WAMD. However, the limitations of this treatment are high costs and invasiveness. For this reason, oral delivery route can be considered as a cost-effective way and the safest method to deliver drug molecules to the eyes. Accordingly, ursodeoxycholic acid (UDCA) was included in the oral formulation as the potential substance for the cure of WAMD in the animal model. Various pharmacological activities, such as antioxidant or anti-inflammatory effects, have been reported for UDCA and recent reports support the effects of UDCA in ocular treatment. However, due to poor water solubility and low pKa (around 5.0), it has been challenging to formulate aqueous solution of UDCA in the neutral pH range. In the present study, we confirmed the aqueous solubility of the oral UDCA formulation and performed a preclinical study, including pharmacokinetic profiling and WAMD model efficacy study in mice after oral administration of the drug solution. The results demonstrated that the formulation improved bioavailability of UDCA and efficiently delivered UDCA to the eye tissues after oral absorption. UDCA formulation was found to have inhibitory effects of choroidal neovascularization with a functional recovery in mice retinas. Taken together, our results suggest that the oral UDCA formulation could be used as a potent supplement for the cure of WAMD and related retinal diseases.

Ursodeoxycholic Acid Halts Pathological Neovascularization in a Mouse Model of Oxygen-Induced Retinopathy

“…Due to the key role of VEGF in promoting RNV in the ischemic retina [45], UDCA's anti-angiogenic effects in OIR mice could be attributable, at least in part, to its effects in halting the VEGF-STAT3 axis by attenuating oxidative/nitrative stress signals in the ischemic retina. Similarly, UDCA has been shown to improve other ocular pathologies that involve excessive VEGF action (or oxidative stress) such as wet age-related macular degeneration [46] and diabetic retinopathy [40], thus, further highlighting the significant impact of UDCA on VEGF signaling.…”

Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Age Related Macular Degeneration, Role in Pathophysiology, and Possible New Therapeutic Strategies

“…This study showed that UDCA formulation not only down-regulated VEGF expression and reduced CNV vascularity and size, but also promoted the functional recovery of the mice retinas according to electroretinography evaluation. Therefore, the authors suggest that UDCA oral formulation could be used as a supplement in cases of exudative AMD thanks to it being a safe and cost-effective way to deliver drug molecules to the eyes [ 132 ].…”

Pharmacological and Metabolic Significance of Bile Acids in Retinal Diseases

“…Woo, et al demonstrated that UDCA and its derivative, TUDCA, when intraperitoneally injected to the laser-treated rat model, could effectively suppress early VEGF elevation in the retina which inhibits the upregulation of VEGF and eventually results in the reduction in CNV size and vascularity, suggesting the possibility of treating CNV [ 101 ]. In a recent study, a mouse model of laser-induced CNV was used to test the efficacy of YSB201 (an aqueous solution of UDCA) in the treatment of AMD [ 102 ]. Results indicated that the YSB201 treatment inhibited the return of angiogenesis to the normal choroidal tissue condition.…”

“…Additionally, while YSB201 treatment at 125 mg/kg/day led to the recovery of retinal function post-injury, the higher dose of YSB201 treatment at 250 mg/kg/day did not yield significantly higher recovery effects. The results of the study specifically describe the inhibitory effects of UDCA formulation on CNV with functional recovery in mice retinas [ 102 ]. Taken together, these results suggest that UDCA could be used as a potent supplement for the cure of AMD and related retinal complications.…”