TWINSTRAND BIOSCIENCES INC — Department of Health and Human Services SBIR Phase I: 102

Description

Development of a Universal Assay for Minimal Residual Disease in Acute Myeloid Leukemia usingDuplex Sequencing Acute myeloid leukemiaAMLis a morbid conditionwith overnew cases anddeaths annually in the U SWhile the majority of patients achieve remissionmost harbor minimal amounts of residual diseaseMRDthat will ultimately lead to relapseThe ability to detect MRD is important as its presence is associated with increased risk of relapse and deathand there is considerable interest in modulating treatment intensity based on the presence or absence of MRDUnfortunatelycurrent MRD detection methods suffer from variable sensitivitynon uniform performance across laboratoriesand lack of broad applicability to all patientsThere is an urgentunmet need for a better MRD detection methodwhich could substantially benefit patients as well as other stakeholdersNext generation sequencingNGSpermits detection of genetic aberrations on the subclonal levelAs virtually all AML harbors mutationsNGS could be a platform for auniversalMRD assayUnlike other detection methodsNGS would reveal specific mutations and could suggest targeted therapiesEnthusiasm for NGS for MRD detection hasuntil nowbeen tempered by the relatively poor sensitivity of this methodDuplex Sequencingthe most accurate NGS technologycan change the paradigm for MRD detectionMembers of our team pioneered this proprietary technology and demonstrated in proof of principal studies that it can accurately detect leukemic clones at extremely low levelsIn Phase I of this Fast Track applicationwe will refine steps in our sequencing procedures to facilitate industrial scale deployment of our MRD assay and validate analytical performanceIn Phase IIwe assess our assayandapos s performance based on banked AML samplesIn Aimwe focus on whether our assay is prognostic of disease relapseIn Aimwe compare our assay to flow cytometrythe current gold standard for MRD detectionIn Aimwe compare performance of our assay on paired bone marrow and peripheral blood samples to determine if we can achieve comparable results less invasivelyThe final product will be a robustcost effectiveand implementable Laboratory Developed TestLDTready for commercial deploymentThis product will be widely useful for patientsoncologistsand payers alike by helping direct cutting edge therapies to the patients most likely to benefitwhile sparing others unnecessary medical and financial toxicitiesIt will allow researchers and pharmaceutical companies to rapidly evaluate novel therapiespermitting future clinical trials to be smaller and less costlyAML takes the lives of thousands of patients every yearPatients die both from the disease and from the aggressive treatmentHaving an ultra accurateuniversaltest to detect MRD would allow for improved prognostication and would pave the way for more efficacious personalized treatmentWe fundamentally believe that such a test is necessary and well within our reachand that our team is positioned better than any other in the world to bring this advance to patients Project Narrative Despite the fact that most patients with acute myeloid leukemia receiving intensive chemotherapy are able to achieve a remissionmany have residual disease below the level of morphological detectionso called `minimal residual diseaseandaposor MRDwhich eventually leads to relapse and ultimately deathCurrent methods of MRD detection are limited in sensitivityare not applicable to all AML patientsand are challenging to perform and interpretThis project proposes to develop an ultra sensitivebroadly applicableand easily implementable MRD assay for patients with acute myeloid leukemia based on Duplex Sequencingthe most sensitive DNA sequencing technology available!