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

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 Phospate M P 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 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 Develop MPS I mice that are immune sensitized to the rhIDU ERT product and 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 PUBLIC HEALTH RELEVANCE The childhood human genetic diseases belonging to the group of lysosomal disorders and bone developmental diseases currently under development at BioStrategies represent some of the most devastating disease afflictions known and the most costly to patients their families and the public health care system Currently available enzyme replacement therapeutics ERTs for several of these diseases although effective for many patients suffer from problems of safety high cost product effectiveness including immune sensitivity problem studied in this project The new therapeutics innovations developed in this SBIR Phase I feasibility project would address many of these issues by developing ERTs that are more effectively targeted to diseased cell types and tissues and that are safer and cheaper to supply to patient populations by virtue of employing newer plant based production technologies The innovative drug delivery technology developed in this project would further the goal of reducing the cost and suffering of patients with these devastating genetic diseases