BIOTISSUE HOLDINGS INC. — Department of Health and Human Services SBIR Phase II: W

Description

Prevention of Proliferative Vitreoretinopathy by HC HA PTX Summary Proliferative vitreoretinopathy PVR is characterized by membranes that develop on the surface of the retina after rhegmatogenous retinal detachments RRD during which time RPE cells are dispersed into the vitreous cavity where they lose contact inhibition and are exposed to multiple growth factors and cytokines This pathological setting promotes proliferation and EMT of RPE cells to fibroblasts or myofibroblasts that produce intravitreal membranes These PVR membranes exert tractional forces on the retina and become the leading cause of failure after RRD surgery Despite additional surgical interventions the visual outcome still remains poor Prevention of PVR during the initial RRD surgery could improve the visual success rate Unfortunately all previous attempts using different agents have been unsuccessful Using an in vitro RPE cell culture model we have reported that following perturbation of contact inhibition of RPE cells EGF and FGF upregulate while TGF downregulates canonical Wnt signaling in the proliferative phase but TGF promotes canonical TGF Smad ZEB signaling in the irreversible scarring phase of EMT We have successfully purified and characterized HC HA PTX from amniotic membrane AM and have reported that this unique matrix is responsible for AMandapos s anti inflammatory anti scarring and anti angiogenic therapeutic actions HC HA PTX is formed by tight association between pentraxin PTX and HC HA which consists of high molecular weight hyaluronic acid HA covalently linked to heavy chain HC of inter trypsin inhibitor I I through the catalytic action of tumor necrosis factor stimulated gene TSG Through Phase I support we have proven the concept that HC HA PTX can be a novel biologic to prevent PVR by inhibiting proliferation and EMT in the aforementioned in vitro model that has been optimized to better mimic in vivo pathological processes of PVR regarding cell density growth factor stimulation and measurement methods We have developed the potency assay that is required as an in process control of the manufacturing of HC HA PTX from different donors demonstrated the safety i e lack of cytotoxicity and the efficacy of HC HA PTX over a wide range of doses demonstrated the efficacy of HC HA PTX but not HA in inhibiting proliferation and gel contraction caused by both ARPE cells and primary human RPE cells and delineated the mode of action of HC HA PTX in inhibiting the aforementioned Wnt and TGF signaling These accomplishments allow us to propose in this Phase II application to scale up the manufacturing of HC HA PTX by combining AM and umbilical cord UC from the same donor Aim to establish the release criteria and the stability of the HC HA PTX formulation via reproducible GMP manufacturing Aim and to determine the safety and efficacy of intravitreal injection of HC HA PTX in our recently established rabbit PVR model Aim Collectively we would like to gather necessary and sufficient pre clinical data for an IND submission to the FDA so that the Company can capture a unique business opportunity by deploying this novel biologic to fulfill the unmet global need of treating this severe retinal blinding disease Narrative Our published data and the Phase I progresses have proven the concept that the HC HA PTX complex purified from human amniotic membrane can suppress proliferation migration gel contraction and EMT of human RPE cells Using an improved in vitro RPE culture model to better mimic the in vivo pathological processes of PVR we have developed the potency assay as an in process control of the manufacturing process of HC HA PTX demonstrated the safety and the efficacy of HC HA PTX in inhibiting both abnormal proliferation and EMT in the optimized in vitro RPE model and delineated the mode of action of HC HA PTX in inhibiting the pathological Wnt and TGF signaling In addition we have reproduced a rabbit PVR model so that in this Phase II application we may scale up the manufacturing of HC HA PTX by combining both AM and umbilical cord UC from the same donor Aim establish the release criteria and the shelf life of the HC HA PTX formulation via reproducible GMP manufacturing Aim and determine the safety and efficacy of intravitreal injection of HC HA PTX in the established rabbit PVR model Aim The successful completion of these three Aims will allow us to gather sufficient pre clinical data for an IND submission to the FDA so that the Company may deploy HC HA PTX as a biologic to treat this serious retinal blinding disease