This invention is a method of promoting lymphangiogenesis in order to treat lymphatic disorders, namely lymphedema and Alzheimer’s disease (AD). VEGFC-induced VEGFR3 signaling is the major driver of lymphangiogenesis, however the distinct molecular mechanisms determining how VEGFR3 signaling controls lymphatic endothelial cell (LEC) fate remains unknown. Our studies demonstrated that ApoA1 binding protein (AIBP) dictates lymphatic vessel formation by accelerating cholesterol efflux and AIBP-regulated cholesterol efflux disrupts lipid rafts/caveolae thereby reducing caveolin-1 (CAV-1) bioavailability. This abolishes the CAV-1 inhibition of VEGFR3 signaling, thereby augmenting VEGFR3 activation and increasing lymphangiogenesis. As a result, our studies demonstrated that therapeutic strategies involving the overexpression of AIBP or inhibition of CAV1 can restore lymphangiogenesis and may be an effective strategy for treating conditions in which the lymphatic function is impaired, such as lymphedema. Additionally, previous studies have shown that meningeal lymphatic dysfunction may be an aggravating factor in AD pathology and age-associated cognitive impairment, thus enhancement of meningeal lymphatic function by targeting the AIBP-CAV1-VEGFR3 axis may be a promising therapeutic opportunity for preventing or delaying age-associated neurological diseases, such as AD. Our data supports the hypothesis that targeting the AIBP-CAV1 axis increases the pro-lymphangiogenesis potential of VEGFC while also limiting the associated neovascularization and vascular leakage.
Stage of Development
In vitro data: We have shown that AIBP enhances VEGFC-engaged VEGFR3 signaling in human lymphatic endothelial cells and AIBP increases the specification of murine lymphatic endothelial cells from embryonic stem cells.
In vivo data: We have shown that AIBP or CAV1 inhibition/modifier peptides consistently augments VEGFC induced corneal lymphangiogenesis in mice. Furthermore, preliminary studies have demonstrated that recombinant AIBP treatment promotes the resolution of secondary tail lymphedema in mice.
Competitive Landscape
There is no cure for lymphedema and treatment strategies generally focus on reducing swelling and controlling pain, such as exercise, compression therapy, massage, and light therapy. Like lymphedema, there is no cure for AD, however, there are a number of pharmacological and non-pharmacological options to alter disease progression and improve quality of life. Despite the vast research in this area, there are currently no approved AD drugs targeting the meningeal lymphatic system. As a result, this therapeutic approach offers a unique first-in-class approach for treating lymphedema and AD.
Competitive Advantages
• Potential for first-in-class designation
Intellectual Property
• Provisional Application Filed on October 13, 2020
• Yang X, Kim J-D, et al. (2020) bioRxiv. doi: 10.1101/2020.10.16.342998
