Development of Next-Generation Precision Medicine RNAi Therapeutics to Treat AML
Development of Next-Generation Precision Medicine RNAi Therapeutics to Treat AML
批准号:
10044943
负责人:
STEVEN F DOWDY
金额:
$40.56万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-07-01 至 2022-06-30
关键词:
Acute Myelocytic LeukemiaAdultAntibodiesAntibody-drug conjugatesCell surfaceCellsChargeChromosomal translocationCleaved cellClinicalCytoplasmDevelopmentDisease remissionDisease-Free SurvivalEndosomesEngineeringGemtuzumab OzogamicinGenesGeneticGenomeGoalsGrowthHematologic NeoplasmsLiverMLL geneMLL-AF9MLLT3 geneMalignant NeoplasmsMasksModelingMonoclonal AntibodiesNormal CellOncogenesOncogenicOutcomePatientsPharmaceutical PreparationsProdrugsPropertyRNA InterferenceRNA Interference TherapyRadioisotopesRelapseSmall Interfering RNATherapeuticTherapeutic AgentsTherapeutic antibodiesTissuesVertebral columnabsorptionacute myeloid leukemia cellanti-PD-1antibody conjugatebasecare outcomeschemical groupchemotherapyfallsfusion genehigh riskin vivoinhibitor/antagonistinorganic phosphateleukemialeukemia/lymphomamouse modelmutantneoplastic cellnext generationnovelpre-clinicalprecision medicineresponsesiRNA deliveryside effectsmall molecule inhibitorstandard of caresuccesstargeted deliverytechnology developmenttherapeutic targetyoung adult
中文摘要
摘要
英文摘要
ABSTRACT
Acute myeloid leukemia (AML) is one of the most prevalent hematological malignancies. Unfortunately,
due to a high relapse rate from chemotherapy, disease-free survival (DFS) remains at 40%. Greater
than 80% of AMLs express high levels of the CD33 marker on their cell surface. Alternative therapeutic
approaches, including Antibody-Drug Conjugate (ADC), anti-CD33 Mylotarg (gemtuzumab ozogamicin),
and Radionuclide Antibody-Conjugates (RACs), have shown some promising results. However, both of
these antibody therapeutic agents have significant side effects and suffer from indiscriminant killing of
normal cells expressing CD33 as well as from killing normal cells due to non-specific tissue absorption
and drug shedding. Unfortunately, AML also does not respond to anti-PD1 and PD-1L check-point
inhibitors. Due to chromosomal translocations, the MLL gene fuses to many other genes, including the
AF9 gene, resulting in MLL-fusion oncogenes that drive AML growth and survival. Expression of MLL-
AF9 driver oncogene in AML has a particularly poor clinical outcome. Consequently, there is a great
need to develop novel precision medicine therapeutics that selectively targets and kills only AML tumor
cells based on their oncogenic genetic translocations, while sparing normal CD33 positive cells. RNA
Interference (RNAi) responses have great potential to target MLL-AF9 and other MLL translocation
fusion genes. Unfortunately, despite its promising therapeutic features, due to their requisite negatively
charged phosphate backbone, siRNAs have no ability to enter cells and require a delivery agent. To
tackle the RNAi delivery problem, we pioneered development of a next-generation RNAi trigger, called
RiboNucleic Neutral (siRNN) prodrugs. siRNNs represent a “Prodrug” approach where the negative
charge is directly neutralized by a bioreversible phosphotriester chemical group that is selectively
cleaved off in the cytoplasm, but not outside of cells. The rate-limiting RNAi delivery step is escape from
the endosome into the cytoplasm. To enhance endosomal escape, we will synthesize a next-generation
endosomal escape domain (EED). We will target delivery of MLL-AF9 siRNN RNAi triggers to AML cells
by conjugation to anti-CD33 antibodies, called Antibody-RNAi Conjugates (ARCs). The goal of this high
risk/high gain technology development proposal is treat AML by generating precision medicine anti-CD33
Antibody-RNAi Conjugates (ARCs) that selectively target the MLL-AF9 fusion oncogene and kill AML
cells based on their mutant genetics, but unlike ADCs and RACs, have no effect on CD33-positive
normal cells.
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会议论文
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批准号:10573227
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项目类别:
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资助金额:$18.1万
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财政年份:2022
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负责人:STEVEN F DOWDY
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依托单位:
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批准号:9228066
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财政年份:2017
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负责人:STEVEN F DOWDY
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依托单位:
Treating Prostate Cancer with RNAi Prodrugs
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批准号:8880847
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资助金额:$20.23万
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财政年份:2015
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负责人:STEVEN F DOWDY
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依托单位:
Novel Cell Cycle Therapeutic Targets in Pancreatic Cancer
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批准号:8511187
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项目类别:
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资助金额:$20.23万
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财政年份:2013
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负责人:STEVEN F DOWDY
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依托单位:
Novel Cell Cycle Therapeutic Targets in Pancreatic Cancer
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批准号:8616738
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项目类别:
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资助金额:$16.35万
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财政年份:2013
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负责人:STEVEN F DOWDY
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依托单位:
ROLE OF CYTOPLASMIC P27KIP1 IN CELL MOTILITY AND METASTASIS
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批准号:7420770
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项目类别:
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资助金额:$0.29万
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财政年份:2006
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负责人:STEVEN F DOWDY
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依托单位:
Transduction of Tumor Suppressor Proteins into Gliomas
-
批准号:6522938
-
项目类别:
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资助金额:$24.89万
-
财政年份:2001
-
负责人:STEVEN F DOWDY
-
依托单位:
Transduction of Tumor Suppressor Proteins into Gliomas
-
批准号:6613762
-
项目类别:
-
资助金额:$24.89万
-
财政年份:2001
-
负责人:STEVEN F DOWDY
-
依托单位:
Transduction of Tumor Suppressor Proteins into Gliomas
-
批准号:6482108
-
项目类别:
-
资助金额:$24.89万
-
财政年份:2001
-
负责人:STEVEN F DOWDY
-
依托单位:
Transduction of Tumor Suppressor Proteins into Gliomas
-
批准号:6929106
-
项目类别:
-
资助金额:$24.89万
-
财政年份:2001
-
负责人:STEVEN F DOWDY
-
依托单位:
Transduction of Tumor Suppressor Proteins into Gliomas
-
批准号:6793571
-
项目类别:
-
资助金额:$24.89万
-
财政年份:2001
-
负责人:STEVEN F DOWDY
-
依托单位:
海外基金