Targeting of Photodynamic Therapy-Resistant Port Wine Birthmarks
Abstract
Vascular malformations are congenital vascular anomalies. They present at birth, grow proportionally with age, and do not regress naturally. They are considered as a result from differentiation impairments of vasculatures including veins, arteries, capillaries, and lymphatic vessels during embryonic development. Vascular malformations cause a variety of severe symptoms, depending on the locations of the lesions, the types of blood vessels involved, and the stage of disease, which makes clinical management very challenging. Development of novel treatments for vascular malformations is among the Strategic Goals in the Fiscal Year 2022 Peer Reviewed Medical Research Program Discovery Award. Port Wine Birthmark (PWB) is one of the most common types of vascular malformations. PWB mainly occurs on the face with initial appearance as flat red macules in childhood; lesions tend to darken progressively to purple and by middle age they often become raised as a result of the development of vascular nodules, which are susceptible to spontaneous bleeding or hemorrhage. The pulsed dye laser (PDL) or photodynamic therapy (PDT) is the common treatment of choice for PWB; unfortunately, complete removal occurs in less than 10% patients treated. These inadequate clinical outcomes mainly result from: (1) incomplete ablation of PWB blood vessels located in the deep dermis where light from the PDL cannot reach effectively, (2) the regrowth of PWB blood vessels post-PDL, and (3) laser-resistant PWB. In order to tackle these challenging clinical barriers, this proposal aims to develop a novel modality referred as a synergistic PDT plus stem cell signaling modulator (SPSM), to achieve an enhanced therapeutic outcome for PWB treatment, particularly laser-resistant PWB lesions. In this proposal, we will take advantages of utilizing our current advancements in the generation of PWB-derived inducible pluripotent stem cells (IPSCs) and their differentiated lineages such as endothelial cells (ECs) as the cell models to design and validate a novel approach of SPSM. These cells present a patient-matching phenotype such as laser resistance and are particularly valuable in the field of vascular malformations for circumventing the lack of animal models. This novel strategy comprises two central components: (1) PDT, to treat PWB blood vessels locating deeply in dermis, and (2) a compound to regulate stem cell laser-resistant phenotypes, thus leading to an enhanced efficacy. Specifically, the following research objectives will be pursued: (1) What is the molecular mechanism underlying SPSM-induced photosensitizing enhancement? (2) What are the optimal parameters to define a SPSM protocol including near infrared (NIR) photosensitizer, stem cell signaling modulator, and laser fluence? This proposed study is highly innovative because it lays the groundwork for a novel approach to the successful treatment of PWB patients with laser-resistant lesions. The formulation of SPSM is novel in stem cell biology and light therapy since no such design has been ever reported. The development of SPSM is very significant because it is designed to directly address the clinical limitations of current treatment of PWB: (1) the NIR wavelength can penetrate deeper into human skin than PDL, thus targeting those blood vessels in the reticular layer of the dermis; (2) a stem cell signaling modulator can manipulate the laser-resistant phenotype, thus leading to an enhanced efficacy in destruction of PWB blood vessels; and (3) the data generated from PWB patient-derived IPSCs and ECs are clinically translational. The SPSM is also of significance as a method for broad new research applications for other types of vascular malformations with serious complications and limited treatment options, such as cerebral arteriovenous malformations, etc.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310008
Entities
People
- Wenbin Tan
Organizations
- United States Army
- University of South Carolina