MPS I Skeletal Disease Therapy with Novel Lectin-delivered Replacement Enzyme

BioStrategies LC is developing the plant galactose binding lectinRTBas an enzyme carrier capable of expanding delivery of enzyme replacement therapiesERTstohardto treatorgans and tissues such as boneThe rare lysosomal disease mucopolysaccharidosis IMPS Iis a progressive multisystem disorderwhich presents with significant skeletal abnormalities that play a major role in patient disease progressionMPS I is caused by genetic deficiencies in the lysosomal enzymeLiduronidaseIDUAwhich is critical for glycosaminoglycan degradationPathological accumulation of dermatan sulfate is particularly problematic in the musculoskeletal system leading to dysostosiscourse facial featuresshort staturearthropathyand joint stiffnessEarly onset formsHurler syndromeare typically treated by bone marrow transplantation and or currently available ERTHowever these treatmentsalone or in combinationdo not adequately correct or arrest skeletal disease progressionPreliminary studies indicate that our RTB IDUA drugIDUALmay deliver the iduronidase lysosomal enzyme to bones of MPS I mouse model animalsThe goal of this proposal is to demonstrate the feasibility of IDUAL to effectively treat the bone and connective tissues in the MPS I mouseSpecific Aims of this proposal are toAssess the impacts of IDUAL treatment on early pathogenic events in MPS I animals during the bone growth phaseandEvaluate molecular and morphometric readouts of MPS I skeletal pathologies during the bone remodeling phase following long term treatment with IDUALBased on these proof of concept resultsPhase II studies would support the scale up manufacturing and rigorous preclinical assessments to move this promising product to an IND approvalThe feasibility established here will also support extending the RTB carrier system to ERTs for other diseases having debilitating musculoskeletal involvement NARRATIVEPUBLIC HEALTH RELEVANCEThe family of human genetic diseases represented by MPS I and other rare lysosomal disordersLDsinclude some of the most devastating human afflictions known and the most costly to patientstheir familiesand the public health systemThe currently approved enzyme replacement therapeuticsERTsavailable to treat several of these diseasesalthough effective for many patientsstill suffer from problems of safetyhigh costavailability of adequate product supplies to patient populationsand product effectiveness in treating all organs of bodyThe new therapeutics technologies for MPS I developed in this SBIR Phase I Randamp D project would address all of these issues by employing new drug delivery technology that more effectively targets affected cell typescellular compartmentsand organsThe need for delivering these new treatment options for treating the skeletal system is particularly critical as current drug options for LDs are generally not effective in bone development diseaseThe innovative drug delivery technology developed in this project including our use of cheaper plant based manufacturing would further the national goal of reducing the suffering and costs for patients afflicted with MPS I and others of these devastating genetic diseases