Kristen M. Kelly - US grants

DESCRIPTION (provided by applicant): Port wine stains (PWS) are congenital, progressive vascular malformations of the skin that occur in approximately 0.7% of neonates and have potentially devastating psychological complications and, in some cases, serious physical effects as well. Current therapies achieve complete blanching of less than 10% of these lesions and multiple treatments (5 -30 or more) are generally required. We intend to combine photodynamic (PDT) and pulsed dye laser (PDL) therapies (PDT + PDL) to achieve permanent destruction of the most clinically relevant PWS blood vessels without injury to the surrounding skin. We will use a vascular specific photosensitizer, benzoporphyrin derivitive monoacid ring A (BPD), and continuous wave (CW) yellow light to confine PDT effects to the most superficial 1.0 mm below the skin surface. Vascular flow will be monitored during PDT using optical Doppler tomography (ODT). CW irradiation will be stopped when a reduction in blood flow is noted or after a light dose of 100 J/cm2 has been delivered. This approach will limit the depth and extent of vascular injury to the targeted vessels and prevent skin necrosis, which would result from total vascular destruction. PDT will be followed immediately, or after a brief time interval, by PDL irradiation to complete superficial vessel destruction without injury to the surrounding skin. Initial experiments using a chick chorioallantoic membrane confirmed the superior efficacy of PDT + PDL PWS vessel destruction as compared to either modality alone. This proposal includes a protocol to confirm the superior efficacy of PDT + PDL using a rat dorsal skin flap window model. The threshold of vascular lesion damage for PDT using BPD and yellow light and optimal treatment parameters for PDT + PDL vascular therapy will also be evaluated using the same animal model. Finally, we will determine the efficacy and safety of PDT + PDL PWS therapy in comprehensive clinical trials. The results of the studies in this proposal are expected to lead to the development of novel and innovative technology which will provide a more effective and, most importantly, safer method for removal of PWS birthmarks.

DESCRIPTION (provided by applicant): We are a group of 10 multi-disciplinary investigators representing 6 departments at the University of California, Irvine with 11 federally funded research grants impacted by this request for instrumentation. We are seeking funds for a multi-wavelength photodynamic therapy (PDT) continuous wave light source to be housed and supported within the well-established NIH-NCRR Biomedical Technology Resource Center (P41-RR01192, Laser Microbeam and Medical Program, LAMMP) at the Beckman Laser Institute. The LAMMP facility is dedicated to defining and understanding broad issues related to the use of light as a diagnostic and therapeutic tool. BLI has been involved in developing, advancing and translating PDT science since the early 1980's and our center has a very strong foundation in technology development. There is an urgent need for a commercial, user-friendly multi-wavelength PDT light source to be housed and managed within our NIH resource. There are very few centers in the United States capable of performing the projects described in this proposal. PDT science is much more advanced in Europe and Asia. The proposed projects were initiated as pilot/feasibility studies using obsolete light sources limiting translation of the PDT science to clinical application. There is a critical need at our center to upgrade and utilize commercially available technology to support this research and to translate our technologies for patient use. Continued progress for these NIH-funded investigators is hampered without access to such an instrument. It is expected that the requested instrumentation will have a significant overall benefit to the UC Irvine research community and beyond, based on the existing strong impact of the LAMMP and its dissemination of new discoveries to colleagues and collaborators.

DESCRIPTION (provided by applicant): Each year 400,000 children are born with port wine stain (PWS) birthmarks. They and their families are confronted with the devastating psychological and physical consequences of this disease. This proposal is a multidisciplinary collaboration between basic and physician scientists designed to improve treatment of pediatric PWS and provide clinical translation of a novel therapeutic regimen, combined photodynamic therapy (PDT) and pulsed dye laser (PDL) treatment (hereafter termed PDT+PDL). Our preliminary data indicate that the combined protocol can enhance the removal of targeted microvasculature. Our long-term goal is to eliminate the physical and psychosocial trauma associated with these lesions. The objective of this application is to investigate the safety and efficacy of PDT+PDL. The central hypothesis is that PDT+PDL will achieve enhanced PWS skin blanching, compared to conventional PDL alone. Our specific aims are to: 1) Identify PDT+PDL therapeutic protocols with clinical applicability;2) Identify candidate mechanisms of action of the PDT+PDL protocol;3) Identify clinically relevant light doses with therapeutic efficacy and 4) Determine clinical outcomes of the selected PDT+PDL protocol on adolescent and adult patients. The proposed translational research is innovative because it will introduce a novel treatment method to the field of pediatric dermatological therapy. The expected outcome is a paradigm shift in the clinical management of PWS birthmarks in order to dramatically improve treatment results. Successfully removing PWS birthmarks in children will eliminate the psychosocial damage these lesions inflict, and will significantly and positively impact the life of affected individuals and their families. Such an outcome will contribute to the NIH mission of methodology development to improve fundamentally the treatment of disease. PUBLIC HEALTH RELEVANCE: The proposed studies evaluating the PDT+PDL protocol are expected to have an important positive impact, providing a more effective and safer method for removal of port wine stain birthmarks (PWS). Successfully removing PWS birthmarks in children will eliminate the psychosocial damage these lesions inflict, and will significantly and positively impact the life of affected individuals and their families.

? DESCRIPTION (provided by applicant): Summary: Multiphoton microscopy (MPM) is a nonlinear laser scanning microscopy technique that features high three-dimensional resolution, fast imaging capabilities and label-free molecular contrast. Several endogenous tissue components can be visualized, including collagen (through second-harmonic generation, SHG), reduced nicotinamide adenine dinucleotide (NADH), flavin adenosine dinucleotide (FAD), keratin, melanin and elastin fibers (through two-photon excited fluorescence, TPEF). The ability to generate high- resolution images of tissue structure and composition without the need for exogenous labels makes MPM imaging particularly well-suited for characterizing superficial tissues in vivo. The purpose of this clinical imaging proposal is to evaluate the ability of in viv multiphoton microscopy to provide quantitative optical endpoints with sufficiently high predictive power to reliably distinguish between pigmented lesions in three groups: common nevi, atypical nevi and melanoma. The framework is based on our preliminary results obtained from a 15-lesion (14 patient) study where we identified three optical biomarkers related to TPEF and SHG signals and correlated these in vivo molecular features with conventional ex vivo histopathologic criteria. MPM biomarkers were combined to obtain a quantitative, 9-point numerical index (multi-photon melanoma index, MMI) that distinguished between common nevi (MMI = 0-1), atypical nevi (MMI = 1-4) and melanoma (MMI = 5-8) (p<0.05). We now propose a powered prospective clinical trial that follows on these promising results in order to determine whether the MMI, or similar MPM-derived index, can be reliably used in a clinical setting. We expect our results will provide a validated decision-making endpoint to increase clinical diagnosis accuracy of common nevi, atypical nevi and melanoma. In addition, our effort to correlate in vivo MPM-derived contrast with conventional histopathology is expected to lead to new insight regarding the origins of melanoma appearance and progression. Our long-term goal is to identify the right combination of quantitative clinical endpoints that would improve clinical diagnoses, guide effective treatment, and eliminate unnecessary biopsies while increasing identification of lesions requiring removal.