JME Group Associates Inc — Department of Health and Human Services SBIR Phase I: NIAMS

Description

Genetic deficiency of lysosomal acid maltase or acid alpha glucosidaseGAAresults in the orphan disease glycogen storage disease type IIGSDIIacid maltase deficiency or Pompeandapos s diseasePDencompassing at least five clinical subtypes of varying severityThe current approved enzyme replacement therapyERTfor PD is via intravenous infusion of a recombinant human GAArhGAAproduced by CHO cellsMyozymeGenzymeonce everyweeksAlthough the current ERT has proven to be efficient in rescuing cardiac abnormalities and extending the life span of infantsthe response in skeletal muscle is variableIn late onset patientsonly mild improvements in motor and respiratory functions have been achieved and the current ERT is unsatisfactory in the reversal of skeletal muscle pathologyDue to the high cost of production of Myozymelifelong treatment can be prohibitively expensiveHenceour objective is to develop an innovative and affordable approach for ERT via oral administrationOral ERTto maintain a sustainedtherapeutic level of enzyme on a daily basis to improve efficacy of treatment and quality of lifeWe have shown that tobrhGAA expressed in the seeds of transgenic tobacco plants is enzymatically active and can correct the enzyme deficiency in GAA deficient cells and in tissues in GAA KO mice by IP adminMartiniuk et alAppl Bio BiotechAdditionallylong term oral treatment showed increased muscle strengthtolerabilitynegligible antibody titersdecreased glycogen levelsincreased GAA in tissues thereby providing support for proof of concept for Oral ERT for Pompe diseaseDaily treatment with whole seeds reversed muscle weakness dose dependentlyPK showed peak tobrhGAA levels athrs in serum andhrs in urinetobrhGAA vs placental GAA enzyme kinetics are very similarAimTo characterize tobrhGAA and in vitro in GAA deficient cellsThe tobrhGAA will be evaluated forenzymatic kineticsuptake by AMD cell lines and compared to placental GAA and Myozyme andNGS genome sequencing proteomics of the tobrhGAAAimOral ERT in GAA KO miceFrom preliminary data in young mice where symptoms are still developingxmg seeds daily achievedrestoration of RW motor activitythusmg should reverse muscle weaknessAdditionallyERT ofmomight be required to maintain reduced glycogen accumulation to reverse the secondary affects of autophagic buildup and blockadeWe will also investigate reversal of more advanced staged disease in older mice ofmoWe will administermg ormg whole seeds daily in the AM to GAA KO miceageandmonthsforandmonthsnper time pointplus controls WT and GAA KO mice treated with WT seeds and GAA KO mice treated with Myozyme IPmg kg wk Genzyme for freeMice will be sacrificed atandmotissuesurine serum are analyzed monitored for reversal of disease by biochemicalclinical presentationhistology and antibody titersExpected feasibility outcomes include increased GAA activity protein in tissues toof normalreversal of clinical phenotypeand decreased glycogenAimPK and ToxicityCRL or Sterling PharmTo address some of the questions by the FDA in our INDa CRO will perform PKtoxicity and maximum tolerated dose in mice and a second non rodent animal rabbit The goal of the proposed research is to investigate the feasibility of a novel approach for enzyme replacementERTvia oral administrationOral ERTwith a recombinant human acid alpha glucosidaserhGAAproduced in transgenic tobacco seeds in an animal model for the orphan disease Pompeandapos s diseaseCompared to infusion of the GAA enzyme once every two weeksthe current approved ERT for Pompeandapos s diseaseOral ERT allows the GAA enzyme to be ingested daily in a pill gel capsule form to maintain a sustainedtherapeutic level of enzyme to improve the efficacy of treatment and quality of life of Pompeandapos s patientsLastlyplant produced GAA enzyme can be produced at a much lower costensuring affordability for lifelong treatment for this devastating disease