Novel nanoparticle based enzyme replacement therapy for Hunter Syndrome

ABSTRACT Significance With overall prevalence of live births lysosomal storage diseases LSD as a class are one of the most common childhood diseases LSD are caused by lysosomal dysfunction mainly due to lysosomal enzyme mutations and are usually fatal in the first two decades of life CNS pathology is present in of LSD however currently marketed enzyme replacement therapy ERT is not effective for LSD with significant CNS pathology because negligible enzyme levels are achieved in brain at therapeutic serum concentrations of enzyme Inefficient enzyme uptake in somatic tissues neutralizing antibody development poor cost effectiveness and weekly IV infusions are other suboptimal attributes Hunter Syndrome caused by X linked iduronate sulfatase I S mutations in male births is associated with severe neuropathology and broad somatic tissue pathology Elaprase human recombinant I S does not address CNS pathology yet is offered to all patients and has sales approaching $ M yearly Intrathecal I S is currently in development Innovation NeuroNano Pharma proposes to develop an innovative polymer based nanoparticle formulation of I S which will be delivered subcutaneously to achieve therapeutic brain levels of I S This product will have a transformative impact on Hunter Syndrome patients and by extension holds promise for application of the technology to other LSD caused by enzyme mutations Approach Preliminary data from Dr Alexander Kabanov s laboratory with PICs containing enzymes shows that brain delivery protection from antibody response and negligible toxicity can be achieved with these formulations After expression and purification at the UNC Center for Structural Biology I S will be incorporated into nanoscale core shell polyion complexes PICs which form spontaneously in aqueous conditions via electrostatic interactions upon mixing of the anionic enzyme with a copolymer consisting of a cationic block and a hydrophilic nonionic block Dr Kabanov and Dr Judy Riffle experts in this field will serve as consultants I S PIC formulations will be characterized with respect to physicochemical properties enzyme activity cytotoxicity lysosome localization and brain levels Two formulations will be selected for full pharmacokinetic characterization by Dr William Banks VA Puget Sound Health Care System a blood brain barrier expert In addition to its own laboratory facilities NNP has access to all necessary equipment through the UNC Nanomedicines Characterization Core Facility Expected Results An optimized I S PIC will be identified that will achieve at least a five fold increase of I S in brain parenchyma and lysosomes compared to free I S and at least serum bioavailability after SC injection Extended serum t and broad somatic tissue uptake compared to free I S is also desirable In phase II the I S PIC will be tested in I S knockout mice to demonstrate enhanced enzyme activity in the brain efficacy against neuropathology and protection from immune response An optimized I S PIC will be scaled up and tested in pre IND GLP toxicology PROJECT NARRATIVE Hunter Syndrome is an X linked lysosomal storage disease which occurs in male births and is caused by mutations in the lysosomal enzyme iduronate sulfatase Current enzyme replacement therapy is inadequate mainly because negligible enzyme levels are achieved in the brain at therapeutic serum concentrations of enzyme and thus neuropathology continues to progress usually resulting in death in the first decades NeuroNano Pharma intends to develop an innovative polymer based nanoparticle formulation of iduronate sulfatase which will be delivered subcutaneously to achieve therapeutic brain levels of iduronate sulfatase and will thereby transform the lives of Hunter Syndrome patients and their families