Oak Lane

INNOVATIVE ORAL REGENERATIVE THERAPY LEVERAGING IMMUNOREGENERATIVE MECHANISMS. - PROJECT SUMMARY FOLLOWING INJURY TO THE LINING OF THE MOUTH, OR THE ORAL MUCOSA, CAUSED BY CLEFT PALATE REPAIR (1:1000 LIVE BIRTHS), WISDOM TEETH REMOVAL (10 MILLION/YEAR) OR TRAUMA (1 MILLION/YEAR), THERE IS A HIGH INCI- DENCE OF WOUND HEALING COMPLICATIONS UP TO 60%. ORAL WOUND HEALING COMPLICATIONS LEAD TO FEEDING, SPEECH, PAIN AND ULTIMATELY SURGERY. ORAL CAVITY WOUND HEALING IS AFFECTED BY PHYSICAL TRAUMA FROM EATING AND OCCURS IN A BACTERIA LADEN ENVIRONMENT. THE LACK OF AN EFFECTIVE REGENERATIVE SOLUTION TO ORAL WOUND HEALING LEADS TO IN- CREASED COST AND MORBIDITY INCLUDING REVISION SURGERIES, CHRONIC PAIN AND MISSED WORKED. CURRENTLY THE ONLY AVAILABLE THERAPIES TO AID ORAL WOUND HEALING INCLUDE ALLOGRAFT DERMAL IMPLANTS, WHICH CARRY THE RISK OF HIV/PRION TRANSMISSION, OR PLATELET RICH PLASMA (PRP). NEITHER HAVE BEEN DEMONSTRATED TO BE EFFECTIVE IN RIGOROUS, CON- TROLLED STUDIES. TO TEST POTENTIAL ORAL REGENERATIVE THERAPIES WE DEVELOPED A MURINE MODEL OF ORAL WOUND HEAL- ING. USING THIS MODEL WE IDENTIFIED AN IMMUNOMODULATORY APPROACH TO IMPROVE THE ORAL HEALING PROCESS. OUR REGENERATIVE SOLUTION DELIVERS FTY720, AN ACTIVE BIOLIPID, THAT TARGETS THE SPHINGOSINE PATHWAY TO PREFERENTIALLY ATTRACT PRO-REGENERATIVE NEUTROPHILS, MONOCYTES AND MACROPHAGES TO CREATE A PRO-REGENERATIVE WOUND HEALING ENVIRONMENT. OUR LONG-TERM GOAL IS TO DEVELOP AN IMMUNOREGENERATIVE APPROACH TO IMPROVE ORAL WOUND HEAL- ING. THE OVERALL OBJECTIVE IN THIS PROPOSAL IS TO COMPARE THE EFFICACY OF FTY720 NANOFIBERS (FTY720-NF) VERSUS PRP TO IMPROVE ORAL WOUND HEALING IN RODENT AND PORCINE ANIMAL MODELS AS A STEP TOWARD CLINICAL TRIALS. THE CENTRAL HYPOTHESIS IS THAT THE DELIVERY OF FTY720-NF ATTRACTS PRO-REGENERATIVE INFLAMMATORY CELLS LEADING TO RE- DUCED INFLAMMATION, INCREASED VASCULARIZATION AND IMPROVED WOUND HEALING. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A COMPREHENSIVE COMPARISON OF FTY720-NF WITH PRP WILL PROVIDE SUFFICIENT DATA TO PROVIDE A STRONG RATIONALE FOR A PHASE II SUBMISSION FOCUSED ON CLINICAL TRIALS. GUIDED BY STRONG PRELIMINARY DATA, INCLUD- ING SEVERAL PUBLICATIONS DEMONSTRATING SIGNIFICANT REDUCTION IN HEALING COMPLICATIONS FOLLOWING FTY720 NANO- FIBER DELIVERY, THE HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: 1) AIM 1: OPTIMIZE AND COMPARE IM- MUNOREGENERATIVE EFFICACY OF FTY720-NF VERSUS PRP FOR ORAL WOUND HEALING IN MICE; 2) AIM 2: TEST THE EFFI- CACY OF FTY720-NF COMPARED TO PRP IN ORAL WOUND HEALING IN MINI-PIGS. IN AIM 1 WE WILL OPTIMIZE THE FTY720-NF SCAFFOLD AND IDENTIFY CHANGES IN INFLAMMATORY CELL RECRUITMENT TO HEALING ORAL MUCOSA AND IDENTIFY THE EXTENT OF ALTERATIONS IN THE VASCULARIZATION AND TISSUE INDUCED BY OF FTY720-NF VS PRP. IN AIM 2, WE WILL TEST THE ABILITY OF FTY720-NF DELIVERY TO DIRECT PRO-REGENERATIVE ORAL WOUND HEALING IN A PORCINE MODEL. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE THE MECHANISMS THAT CHARACTERIZE ORAL WOUND HEALING IN RODENT AND PORCINE MODELS INDUCED BY FTY720-NF AND PRP HAVE NOT BEEN INVESTIGATED BEFORE. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE FTY720, AN ALREADY FDA-APPROVED DRUG APPROVED TO TREAT MULTIPLE SCLEROSIS, COULD BE FAST TRACKED TO CLINICAL TRIALS TO REDUCE ONF FORMATION.

INNOVATIVE ORAL REGENERATIVE THERAPY LEVERAGING IMMUNOREGENERATIVE MECHANISMS. - PROJECT SUMMARY FOLLOWING INJURY TO THE LINING OF THE MOUTH, OR THE ORAL MUCOSA, CAUSED BY CLEFT PALATE REPAIR (1:1000 LIVE BIRTHS), WISDOM TEETH REMOVAL (10 MILLION/YEAR) OR TRAUMA (1 MILLION/YEAR), THERE IS A HIGH INCI- DENCE OF WOUND HEALING COMPLICATIONS UP TO 60%. ORAL WOUND HEALING COMPLICATIONS LEAD TO FEEDING, SPEECH, PAIN AND ULTIMATELY SURGERY. ORAL CAVITY WOUND HEALING IS AFFECTED BY PHYSICAL TRAUMA FROM EATING AND OCCURS IN A BACTERIA LADEN ENVIRONMENT. THE LACK OF AN EFFECTIVE REGENERATIVE SOLUTION TO ORAL WOUND HEALING LEADS TO IN- CREASED COST AND MORBIDITY INCLUDING REVISION SURGERIES, CHRONIC PAIN AND MISSED WORKED. CURRENTLY THE ONLY AVAILABLE THERAPIES TO AID ORAL WOUND HEALING INCLUDE ALLOGRAFT DERMAL IMPLANTS, WHICH CARRY THE RISK OF HIV/PRION TRANSMISSION, OR PLATELET RICH PLASMA (PRP). NEITHER HAVE BEEN DEMONSTRATED TO BE EFFECTIVE IN RIGOROUS, CON- TROLLED STUDIES. TO TEST POTENTIAL ORAL REGENERATIVE THERAPIES WE DEVELOPED A MURINE MODEL OF ORAL WOUND HEAL- ING. USING THIS MODEL WE IDENTIFIED AN IMMUNOMODULATORY APPROACH TO IMPROVE THE ORAL HEALING PROCESS. OUR REGENERATIVE SOLUTION DELIVERS FTY720, AN ACTIVE BIOLIPID, THAT TARGETS THE SPHINGOSINE PATHWAY TO PREFERENTIALLY ATTRACT PRO-REGENERATIVE NEUTROPHILS, MONOCYTES AND MACROPHAGES TO CREATE A PRO-REGENERATIVE WOUND HEALING ENVIRONMENT. OUR LONG-TERM GOAL IS TO DEVELOP AN IMMUNOREGENERATIVE APPROACH TO IMPROVE ORAL WOUND HEAL- ING. THE OVERALL OBJECTIVE IN THIS PROPOSAL IS TO COMPARE THE EFFICACY OF FTY720 NANOFIBERS (FTY720-NF) VERSUS PRP TO IMPROVE ORAL WOUND HEALING IN RODENT AND PORCINE ANIMAL MODELS AS A STEP TOWARD CLINICAL TRIALS. THE CENTRAL HYPOTHESIS IS THAT THE DELIVERY OF FTY720-NF ATTRACTS PRO-REGENERATIVE INFLAMMATORY CELLS LEADING TO RE- DUCED INFLAMMATION, INCREASED VASCULARIZATION AND IMPROVED WOUND HEALING. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A COMPREHENSIVE COMPARISON OF FTY720-NF WITH PRP WILL PROVIDE SUFFICIENT DATA TO PROVIDE A STRONG RATIONALE FOR A PHASE II SUBMISSION FOCUSED ON CLINICAL TRIALS. GUIDED BY STRONG PRELIMINARY DATA, INCLUD- ING SEVERAL PUBLICATIONS DEMONSTRATING SIGNIFICANT REDUCTION IN HEALING COMPLICATIONS FOLLOWING FTY720 NANO- FIBER DELIVERY, THE HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: 1) AIM 1: OPTIMIZE AND COMPARE IM- MUNOREGENERATIVE EFFICACY OF FTY720-NF VERSUS PRP FOR ORAL WOUND HEALING IN MICE; 2) AIM 2: TEST THE EFFI- CACY OF FTY720-NF COMPARED TO PRP IN ORAL WOUND HEALING IN MINI-PIGS. IN AIM 1 WE WILL OPTIMIZE THE FTY720-NF SCAFFOLD AND IDENTIFY CHANGES IN INFLAMMATORY CELL RECRUITMENT TO HEALING ORAL MUCOSA AND IDENTIFY THE EXTENT OF ALTERATIONS IN THE VASCULARIZATION AND TISSUE INDUCED BY OF FTY720-NF VS PRP. IN AIM 2, WE WILL TEST THE ABILITY OF FTY720-NF DELIVERY TO DIRECT PRO-REGENERATIVE ORAL WOUND HEALING IN A PORCINE MODEL. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE THE MECHANISMS THAT CHARACTERIZE ORAL WOUND HEALING IN RODENT AND PORCINE MODELS INDUCED BY FTY720-NF AND PRP HAVE NOT BEEN INVESTIGATED BEFORE. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE FTY720, AN ALREADY FDA-APPROVED DRUG APPROVED TO TREAT MULTIPLE SCLEROSIS, COULD BE FAST TRACKED TO CLINICAL TRIALS TO REDUCE ONF FORMATION.

INNOVATIVE ORAL REGENERATIVE THERAPY LEVERAGING IMMUNOREGENERATIVE MECHANISMS. - PROJECT SUMMARY FOLLOWING INJURY TO THE LINING OF THE MOUTH, OR THE ORAL MUCOSA, CAUSED BY CLEFT PALATE REPAIR (1:1000 LIVE BIRTHS), WISDOM TEETH REMOVAL (10 MILLION/YEAR) OR TRAUMA (1 MILLION/YEAR), THERE IS A HIGH INCI- DENCE OF WOUND HEALING COMPLICATIONS UP TO 60%. ORAL WOUND HEALING COMPLICATIONS LEAD TO FEEDING, SPEECH, PAIN AND ULTIMATELY SURGERY. ORAL CAVITY WOUND HEALING IS AFFECTED BY PHYSICAL TRAUMA FROM EATING AND OCCURS IN A BACTERIA LADEN ENVIRONMENT. THE LACK OF AN EFFECTIVE REGENERATIVE SOLUTION TO ORAL WOUND HEALING LEADS TO IN- CREASED COST AND MORBIDITY INCLUDING REVISION SURGERIES, CHRONIC PAIN AND MISSED WORKED. CURRENTLY THE ONLY AVAILABLE THERAPIES TO AID ORAL WOUND HEALING INCLUDE ALLOGRAFT DERMAL IMPLANTS, WHICH CARRY THE RISK OF HIV/PRION TRANSMISSION, OR PLATELET RICH PLASMA (PRP). NEITHER HAVE BEEN DEMONSTRATED TO BE EFFECTIVE IN RIGOROUS, CON- TROLLED STUDIES. TO TEST POTENTIAL ORAL REGENERATIVE THERAPIES WE DEVELOPED A MURINE MODEL OF ORAL WOUND HEAL- ING. USING THIS MODEL WE IDENTIFIED AN IMMUNOMODULATORY APPROACH TO IMPROVE THE ORAL HEALING PROCESS. OUR REGENERATIVE SOLUTION DELIVERS FTY720, AN ACTIVE BIOLIPID, THAT TARGETS THE SPHINGOSINE PATHWAY TO PREFERENTIALLY ATTRACT PRO-REGENERATIVE NEUTROPHILS, MONOCYTES AND MACROPHAGES TO CREATE A PRO-REGENERATIVE WOUND HEALING ENVIRONMENT. OUR LONG-TERM GOAL IS TO DEVELOP AN IMMUNOREGENERATIVE APPROACH TO IMPROVE ORAL WOUND HEAL- ING. THE OVERALL OBJECTIVE IN THIS PROPOSAL IS TO COMPARE THE EFFICACY OF FTY720 NANOFIBERS (FTY720-NF) VERSUS PRP TO IMPROVE ORAL WOUND HEALING IN RODENT AND PORCINE ANIMAL MODELS AS A STEP TOWARD CLINICAL TRIALS. THE CENTRAL HYPOTHESIS IS THAT THE DELIVERY OF FTY720-NF ATTRACTS PRO-REGENERATIVE INFLAMMATORY CELLS LEADING TO RE- DUCED INFLAMMATION, INCREASED VASCULARIZATION AND IMPROVED WOUND HEALING. THE RATIONALE FOR THE PROPOSED RESEARCH IS THAT A COMPREHENSIVE COMPARISON OF FTY720-NF WITH PRP WILL PROVIDE SUFFICIENT DATA TO PROVIDE A STRONG RATIONALE FOR A PHASE II SUBMISSION FOCUSED ON CLINICAL TRIALS. GUIDED BY STRONG PRELIMINARY DATA, INCLUD- ING SEVERAL PUBLICATIONS DEMONSTRATING SIGNIFICANT REDUCTION IN HEALING COMPLICATIONS FOLLOWING FTY720 NANO- FIBER DELIVERY, THE HYPOTHESIS WILL BE TESTED BY PURSUING TWO SPECIFIC AIMS: 1) AIM 1: OPTIMIZE AND COMPARE IM- MUNOREGENERATIVE EFFICACY OF FTY720-NF VERSUS PRP FOR ORAL WOUND HEALING IN MICE; 2) AIM 2: TEST THE EFFI- CACY OF FTY720-NF COMPARED TO PRP IN ORAL WOUND HEALING IN MINI-PIGS. IN AIM 1 WE WILL OPTIMIZE THE FTY720-NF SCAFFOLD AND IDENTIFY CHANGES IN INFLAMMATORY CELL RECRUITMENT TO HEALING ORAL MUCOSA AND IDENTIFY THE EXTENT OF ALTERATIONS IN THE VASCULARIZATION AND TISSUE INDUCED BY OF FTY720-NF VS PRP. IN AIM 2, WE WILL TEST THE ABILITY OF FTY720-NF DELIVERY TO DIRECT PRO-REGENERATIVE ORAL WOUND HEALING IN A PORCINE MODEL. THE PROPOSED RESEARCH IS INNOVATIVE BECAUSE THE MECHANISMS THAT CHARACTERIZE ORAL WOUND HEALING IN RODENT AND PORCINE MODELS INDUCED BY FTY720-NF AND PRP HAVE NOT BEEN INVESTIGATED BEFORE. THE PROPOSED RESEARCH IS SIGNIFICANT BECAUSE FTY720, AN ALREADY FDA-APPROVED DRUG APPROVED TO TREAT MULTIPLE SCLEROSIS, COULD BE FAST TRACKED TO CLINICAL TRIALS TO REDUCE ONF FORMATION.