Project Grant R44TR004557

A CROSS-SPECIES PRECLINICAL PLATFORM TO ENHANCE THE TRANSLATION OF NEW MEDICINES - PROJECT DESCRIPTION DUCHENNE MUSCULAR DYSTROPHY (DMD) IS A LETHAL, X-LINKED RECESSIVE DISORDER WITH NO KNOWN CURE THAT AFFLICTS 1 IN 5,000 NEWBORN MALES. PATIENTS CARRY A MUTATION IN THE DYSTROPHIN (DMD) GENE, RESULTING IN ABERRANT OR ABSENT EXPRESSION OF THE DYSTROPHIN PROTEIN. AFFECTED INDIVIDUALS EXPERIENCE PROGRESSIVE WASTING OF SKELETAL MUSCLES AND CARDIAC DYSFUNCTION LEADING TO LOSS OF AMBULATION AND PREMATURE DEATH, PRIMARILY DUE TO CARDIAC OR RESPIRATORY FAILURE. ONLY PALLIATIVE TREATMENTS ARE AVAILABLE, ALTHOUGH GENE THERAPY APPROACHES FOR DMD HAVE BEEN EFFECTIVELY APPLIED IN DYSTROPHIC ANIMAL MODELS BY EITHER DIRECTLY TARGETING A CLASS OF MUTATIONS (AS WITH EXON SKIPPING OR GENE EDITING) OR BY DELIVERING A SYNTHETIC VERSION OF THE DYSTROPHIN GENE. THE LACK OF SCALABLE, HUMAN- BASED PRE-CLINICAL SCREENING MODELS IS A SIGNIFICANT ROADBLOCK TO DEVELOPING NEW THERAPIES FOR THESE PATIENTS. SIMPLE SINGLE MOLECULE ASSAYS CAN BE READILY SCALED, BUT LACK THE COMPLEXITY NEEDED TO MODEL MUSCLE CONTRACTION WHICH RELIES ON A SYMPHONY OF MANY BIOLOGICAL SYSTEMS WORKING IN CONCERT TO PRODUCE MOVEMENT. AT THE OTHER END OF THE SPECTRUM, ANIMAL (PARTICULARLY MOUSE) MODELS HAVE GENERATED MUCH THAT IS KNOWN ABOUT THE DISEASE, BUT THEY ARE COSTLY, SLOW, AND IN NOTABLE INSTANCES HAVE GIVEN FALSE POSITIVES FOR NEW TREATMENTS THAT FAILED TO TRANSLATE TO HUMANS. IN THIS FASTTRACK SBIR PROPOSAL, CURI BIO AND ITS PARTNERS WILL DEVELOP A NOVEL PRECLINICAL SCREENING PLATFORM FOR DMD THAT DIRECTLY MEASURES THE CONTRACTION OF STEM CELL-DERIVED MUSCLE TISSUE CONSTRUCTS FROM BOTH HUMAN AND MURINE CELLS. BECAUSE THE CONTRACTILITY OF TISSUE CONSTRUCTS IS DIRECTLY MEASURED, THERAPIES CAN BE TESTED IN THE COMPLEX CONTEXT OF THE MOSAIC OF PHENOTYPES THAT CONSTITUTE MUSCLE CONTRACTION. FURTHER, THE USE OF BOTH MURINE AND HUMAN CELLS WILL ALLOW DIRECT COMPARISON OF RESULTS TO UNDERSTAND SPECIES- SPECIFIC BIOLOGY AS WELL AS TO TRANSLATE PAST RESULTS FROM ANIMAL MODELS. SUCCESSFUL COMPLETION OF THIS PROPOSAL WILL VALIDATE THE PLATFORM'S ABILITY TO MODEL CONTRACTILE DYSFUNCTION IN THE DISH, AND TO MEASURE THE DEGREE OF RECOVERY AFTER APPLICATION OF A NOVEL THERAPEUTIC STRATEGY THAT HAS BEEN SHOWN TO RESTORE THE EXPRESSION OF HEALTHY DYSTROPHIN IN PATIENT CELLS. THE COMPANY WILL ALSO LEVERAGE THIS PLATFORM BY MEASURING THE THERAPEUTIC EFFECT OF A REVOLUTIONARY ADENO-ASSOCIATED VIRUS-BASED GENE THERAPY THAT WILL BE SUPERIOR IN BOTH SAFETY AND EFFICACY COMPARED TO CURRENT APPROACHES. THE DELIVERABLES OF THIS PROJECT WILL GREATLY IMPROVE THE FIELD'S ABILITY TO PRECLINICALLY TEST NOVEL THERAPEUTICS AND WILL SPEED TO MARKET NEW LIFESAVING DRUGS FOR DEVASTATING DISEASES.