Enzyme Replacement Therapeutics for Rare Childhood Genetic Diseases: An ERT Delivery System that Mitigates Immune-sensitization

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 DESCRIPTION (provided by applicant): The goal of this proposal is to develop an enzyme replacement therapy (ERT) approach for rare genetic diseases that is effective in mitigating the problem of immune sensitization that has hindered previous ERT technologies. Enzyme replacement therapies remain the most effective treatment for those rare genetic diseases for which approved recombinant enzyme products are available. ERTs have been crucial in treating several lysosomal diseases (LDs), which in their severe forms present with devastating multi-organ pathologies in affected children. However, the induction of patient anti-ERT antibodies (immune sensitization) has emerged as a significant limitation in the effectiveness of ERTs, altering enzyme distribution and activity. Because early/infantile-onset forms comprise the most severe mutations, the development of immune sensitization is much more prevalent in younger patients. These children often show dramatic life-saving improvements upon treatment onset. However, progress stops or quickly declines as these patients develop neutralizing antibodies to the ERT drug. Most currently approved ERTs for LDs exploit the same Mannose-6-Phospate (M6P) receptor for uptake into disease cells and the predominant class of anti-ERT antibodies interfere with this uptake process. However, the ERT technology developed by BioStrategies LC uses an alternative ERT-RTB fusion mechanism for cell uptake and we have found in preliminary experiments using Hurler MPS I lysosomal disease cell cultures that active ERT-RTB was successfully delivered in the presence of neutralizing antibody containing serum from immune-sensitized animals. Based on these promising in vitro results, our goal in this SBIR Phase 1 is to demonstrate in vivo efficacy, including enzyme delivery and glucosaminoglycan (GAG) substrate reduction, in ERT-sensitized Hurler mice. We previously demonstrated that IDUA: RTB shows broad bio-distribution and corrects GAG substrate levels in the MPS I mouse model. Specific aims for Phase I include to: 1) Develop MPS I mice that are immune sensitized to the rhIDU ERT product and 2) Compare IDUA activity and GAG levels in selected tissues in rhIDU-sensitized mice following treatments with either rhIDU or IDUA:RTB. Success of these experiments will demonstrate that a significant increase of ERT enzyme activity is delivered to organs of IDUA sensitized Hurler mice after treatment with IDUA-RTB verses rhIDU. Based on a successful Phase I feasibility study, Phase II research will target statistically significant assessments in the MSP I animal model and application of the RTB lectin platform to other diseases such as Pompe and other diseses where immune sensitization problems have most significantly impacted successful ERT treatments. The long-term goal is to develop new immune mitigating ERTs for patients that will provide sustainable efficacy of these therapies for lysosomal and other protein deficiency diseases.