A Modality-Agnostic Potency Assay Enabling Both Ex Vivo and In Vivo Genome Editing Therapeutics for Sickle Cell Disease
一种与模态无关的效力测定,可实现镰状细胞病的体外和体内基因组编辑治疗
基本信息
- 批准号:10668694
- 负责人:
- 金额:$ 48.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-28 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:Abnormal HemoglobinsAbnormal Red Blood CellAddressAffectAmericanBiological AssayBiophysicsBlood capillariesCellsChemistryClinicalClinical TrialsCodeDNA sequencingDataDevelopmentDevicesDiagnosticDiagnostic EquipmentDiseaseErythrocytesEventExhibitsFDA approvedFeedbackGenesHealthHematological DiseaseHematologyHematopoietic stem cellsHemoglobinHigh Pressure Liquid ChromatographyHumanIn VitroIndividualInheritedLabelLaboratoriesLife ExpectancyLinear RegressionsMachine LearningMeasuresMethodsMicrofluidicsModalityModelingModificationMolecularMorbidity - disease rateOrganOrgan failureOutcomeOutputPainPathologicPatientsPerformancePharmaceutical PreparationsPhenotypePolymersPopulationPositioning AttributePropertyProtocols documentationReference StandardsRegulationResearch Project GrantsResolutionSamplingSeveritiesSickle Cell AnemiaSourceTestingTrainingValidationVariantalgorithm trainingassay developmentautosomebase editingbiochipbiophysical propertiescell preparationclinical developmentclinically relevantcohortdiagnostic assaydiagnostic tooldisease phenotypeexperiencegene therapygenome editinghealth assessmentimprovedin vivoinnovationlaboratory equipmentmachine learning modelmanufacturemortalityneural networknext generationnovelpersonalized diagnosticspolymerizationprimary endpointrepairedresponsesimulationsupervised learningtherapeutic genome editingvaso-occlusive pain
项目摘要
ABSTRACT / PROJECT SUMMARY
Sickle-cell disease (SCD) is an autosomal recessive disorder that causes considerable
morbidity and mortality, affecting an estimated 100,000 individuals in the US, and millions more
worldwide. Multiple editing-based cures for SCD are currently in clinical development, however,
there are no clinical-grade laboratory tests available capable of characterizing the biophysical
and rheological properties of RBCs derived from genome-edited SCD HSPCs. Assays capable
of characterizing RBC quality are urgently needed to assess the potency of emerging
editing-based genomic therapies for SCD, regardless of the editing modality.
One of the central challenges that has impeded the development of a highly performant
potency assay for evaluating the functional efficacy of editing-based genomic therapies for SCD
has been the lack of laboratory technologies capable of sensitively, accurately, and precisely
capturing the biophysical properties of SCD-RBCs utilizing only a small number of cells. In
recent years, several innovations have emerged that now make the development and analytical
validation of a potency assay for editing-based SCD genomic therapies feasible. One of these
has been the advent of microfluidics-based diagnostic devices capable of functionally
characterizing the health of RBCs at unprecedented levels of resolution and sensitivity.
This proposal seeks to leverage (1) an existing suite of these aforementioned
next-generation RBC biophysical and functional characterization devices, (2) conventional
hematologic assays, and (3) a well-established machine learning approach to develop and
analytically validate a first-in-kind potency assay for editing-based therapies for SCD. To
achieve this, we will first construct a panel of comprehensively profiled, gold-standard reference
samples of HSPCs that simulate a representative range of genome editing outcomes in SCD
and prepare data for machine learning training. A machine learning model will then be trained to
predict the percentage of RBCs that functionally exhibit a non-SCD phenotype. Once trained,
we will validate the performance of the new potency assay, a panel of HSPCs affected by SCD
will be therapeutically edited using at least three different modalities (e.g. homology-directed
repair, base-editing, etc.).
摘要/项目总结
镰状细胞病(SCD)是一种常染色体隐性遗传疾病,
发病率和死亡率,影响美国估计10万人,数百万人
国际吧多种基于编辑的SCD治疗目前正在临床开发中,然而,
没有临床级的实验室测试能够表征生物物理学
和源自基因组编辑的SCD HSPC的RBC的流变性质。检测试剂盒
红细胞质量的特征,迫切需要评估新兴的潜力,
用于SCD的基于编辑的基因组疗法,无论编辑方式如何。
阻碍开发高性能
用于评估SCD的基于编辑的基因组疗法的功能功效的效力测定
缺乏能够灵敏、准确和精确地
仅利用少量细胞捕获SCD-RBC的生物物理特性。在
近年来,出现了一些创新,现在使发展和分析
验证基于编辑的SCD基因组疗法的效力测定是可行的。其中一
基于微流体的诊断设备的出现,
以前所未有的分辨率和灵敏度表征RBC的健康状况。
该提案旨在利用(1)上述现有套件
下一代RBC生物物理和功能表征装置,(2)常规
血液学测定,和(3)完善的机器学习方法来开发和
分析验证SCD基于编辑疗法的首个同类效价测定。到
要做到这一点,我们将首先建立一个全面介绍,黄金标准的参考小组,
模拟SCD中代表性范围的基因组编辑结果的HSPC样品
并为机器学习训练准备数据。然后,机器学习模型将被训练成
预测在功能上表现出非SCD表型的RBC的百分比。一旦接受训练,
我们将验证新效价测定的性能,即一组受SCD影响的HSPC
将使用至少三种不同的方式(例如同源定向的
修复、基础编辑等)。
项目成果
期刊论文数量(0)
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