Restoring Vision with High-Fidelity Nonsense Codon Correction
通过高保真无义密码子校正恢复视力
基本信息
- 批准号:10550272
- 负责人:
- 金额:$ 146.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-02-01 至 2025-11-30
- 项目状态:未结题
- 来源:
- 关键词:AccountingAddressAmino AcidsAnatomyAnticodonBiochemicalBiological AssayBiological AvailabilityBiological ModelsBlindnessCell Differentiation processCell membraneCellsChildhoodClinical TrialsCommunicationCommunitiesComplexCone dystrophyCultured CellsDNADNA SequenceDataDefectDevelopmentDiseaseDrug Delivery SystemsDrug TargetingElectrophysiology (science)EngineeringEvaluationEyeEye diseasesFDA approvedGenesGenetic DiseasesGlutamineHumanIn VitroIncidenceInheritedIon ChannelIon Channel ProteinIowaLibrariesLightLocationMembrane ProteinsMethodsMissense MutationMolecularMonitorMusMutationNeural RetinaNight BlindnessNonsense CodonNonsense MutationNucleotidesOphthalmologistOrganoidsPathogenesisPatientsPharmaceutical PreparationsPhotoreceptorsPhototransductionPhysiologyPoint MutationPost-Translational Protein ProcessingProductionProtein BiosynthesisProtein TruncationProtein translocationProteinsProteomicsRNA deliveryRNA-targeting therapyResearchResearch PersonnelResourcesRetinaRetinal DiseasesRetinal PhotoreceptorsRibosomesScientistSilicon DioxideSiteStructureStructure of retinal pigment epitheliumSystemTRPM1 geneTechnologyTerminator CodonTestingTherapeuticTherapeutic InterventionTissuesToxic effectTransfer RNATranslationsUniversitiesViralVitelliform macular dystrophybasecell typedisease phenotypeefficacious treatmentfunctional outcomesgene therapygenome editinghuman diseasehuman pluripotent stem cellin vivoinduced pluripotent stem cellintravitreal injectionmouse modelnanomaterialsnanomedicinenanoparticlenew technologynext generationnonhuman primatenovelnucleic acid-based therapeuticspharmacologicpolypeptidepre-clinicalpre-clinical therapypreclinical safetyprematurerepairedretinal progenitor cellsafety assessmentsafety testingsight restorationsmall moleculesmall molecule therapeuticsstem cell biologytargeted deliverytherapeutic RNAtherapeutic genetranscriptomicsvirtual
项目摘要
PROJECT SUMMARY/ABSTRACT
Nonsense mutations cause approximately 15% of genetically inherited retinopathies and inherited human
diseases in general, accounting for 2.5 to 3 million patients in the U.S. For certain specific genes, nonsense
mutation incidences can be as high as 40%. Because nonsense mutations cause premature termination (PTC)
of protein translation, the disease phenotype is often severe. Currently, there are only a limited number of
therapies for nonsense mutations being tested in human clinical trials, including gene therapy, small molecule
read-through drugs, or genome editing. Associated challenges equal the promises of each of these therapeutic
options. Looking forward, newer technologies may address these hurdles and provide more safe and efficacious
treatments for patients. During protein translation, tRNA functions at the ribosomal site to incorporate a specific
amino acid into the polypeptide sequence. We aim to develop the next generation of nucleic acid therapy based
on anticodon encoding transfer RNA (ace-tRNA) that incorporates the correct wild type amino acid at the site of
a disease-causing nonsense mutation. Because of the many anatomical advantages afforded by the eye, we
seek to test the broad applicability of ace-tRNA therapeutics for nonsense mutations that cause retinopathies
and related blindness due to defects in a variety of genes, including those encoding ion channel proteins.
Specifically we will focus on nonsense mutation in ion channels expressed in photoreceptors (PR) which convert
retinal light inputs and retinal pigment epithelium (RPE), which provide support for PR. These two cell types are
primarily the site of blindness pathogenesis.
In this project, we will:
1) Develop ace-tRNA therapeutics that target specific nonsense mutations across several PR and RPE ion
channels.
2) Engineer both viral and non-viral ace-tRNA delivery systems for long-term editing. Using these we will
determine the functional outcome of ace-tRNA treatment using cultured cells and human iPSC-derived
RPE and iPSC-PR retinal organoids.
3) Test both our viral and non-viral ace-tRNA in vivo using mice harboring genetic defects that cause
blindness in humans; and
4) Assess the safety and bioavailability of ace-tRNA therapeutics in our preclinical NHP model systems.
There are no FDA-approved therapeutic drugs that target channelopathies because of the complexities
associated with precise post-translational modifications, carefully regulated expression, and assembly. Our
team’s combined expertise in ace-tRNA development, nanomaterial synthesis, human pluripotent stem cell
biology, ion-channel physiology, and pathophysiological model systems is unique and ideally suited to advance
ace-tRNA technology toward clinical trials for a wide range of genetic diseases that cause blindness.
项目总结/摘要
无义突变导致大约15%的遗传性视网膜病和遗传性人类视网膜病变。
一般来说,美国有250万到300万患者患有这种疾病。
突变发生率可高达40%。因为无义突变会导致早产(PTC)
由于蛋白质翻译的限制,疾病表型通常是严重的。目前,只有有限数量的
在人类临床试验中测试的无义突变疗法,包括基因疗法,小分子
通读药物或基因组编辑。相关的挑战等于这些治疗方法的承诺
选项.展望未来,更新的技术可能会解决这些障碍,并提供更安全有效的
患者的治疗。在蛋白质翻译过程中,tRNA在核糖体位点起作用,将特定的
将氨基酸插入多肽序列中。我们的目标是开发下一代的核酸治疗,
反密码子编码转移RNA(ace-tRNA),其在以下位点掺入正确的野生型氨基酸:
一种致病的无意义突变由于眼睛提供的许多解剖学优势,我们
试图测试ace-tRNA疗法对导致视网膜病变的无义突变的广泛适用性
以及由于包括编码离子通道蛋白的基因在内的多种基因的缺陷而导致的相关失明。
具体来说,我们将集中在光感受器(PR)中表达的离子通道中的无义突变,
视网膜光输入和视网膜色素上皮(RPE),为PR提供支持。这两种细胞类型是
主要是失明发病的部位。
在这个项目中,我们将:
1)开发针对几种PR和RPE离子的特异性无义突变的ace-tRNA疗法
渠道
2)设计用于长期编辑的病毒和非病毒ace-tRNA递送系统。利用这些,我们将
使用培养的细胞和人iPSC衍生的细胞来确定ace-tRNA治疗的功能结果。
RPE和iPSC-PR视网膜类器官。
3)测试我们的病毒和非病毒ace-tRNA在体内使用小鼠窝藏遗传缺陷,导致
人类失明;以及
4)在我们的临床前NHP模型系统中评估ace-tRNA治疗剂的安全性和生物利用度。
由于复杂性,没有FDA批准的针对通道病的治疗药物
与精确的翻译后修饰、仔细调控的表达和组装相关。我们
团队在ace-tRNA开发、纳米材料合成、人类多能干细胞
生物学、离子通道生理学和病理生理学模型系统是独特的,非常适合于发展
ace-tRNA技术用于临床试验,用于广泛的导致失明的遗传疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christopher A Ahern其他文献
Christopher A Ahern的其他文献
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{{ truncateString('Christopher A Ahern', 18)}}的其他基金
Chemical biology of voltage-gated cation channels
电压门控阳离子通道的化学生物学
- 批准号:
10552311 - 财政年份:2023
- 资助金额:
$ 146.02万 - 项目类别:
A Versatile Chemical-Genetic Approach to Determine Bases for Arrhythmogenesis and Sodium Channelopathies
确定心律失常发生和钠离子通道病基础的多功能化学遗传学方法
- 批准号:
10608370 - 财政年份:2022
- 资助金额:
$ 146.02万 - 项目类别:
Restoring Vision with High-Fidelity Nonsense Codon Correction
通过高保真无义密码子校正恢复视力
- 批准号:
10334544 - 财政年份:2021
- 资助金额:
$ 146.02万 - 项目类别:
Restoring Vision with High-Fidelity Nonsense Codon Correction
通过高保真无义密码子校正恢复视力
- 批准号:
10156779 - 财政年份:2021
- 资助金额:
$ 146.02万 - 项目类别:
Restoring Vision with High-Fidelity Nonsense Codon Correction
通过高保真无义密码子校正恢复视力
- 批准号:
10407714 - 财政年份:2021
- 资助金额:
$ 146.02万 - 项目类别:
Restoring Vision with High-Fidelity Nonsense Codon Correction
通过高保真无义密码子校正恢复视力
- 批准号:
10627046 - 财政年份:2021
- 资助金额:
$ 146.02万 - 项目类别:
Mining the tRNA genome by live-cell imaging
通过活细胞成像挖掘 tRNA 基因组
- 批准号:
10005950 - 财政年份:2019
- 资助金额:
$ 146.02万 - 项目类别:
Photochemical determination of sodium channel voltage-dependent gating and composition
钠通道电压依赖性门控和成分的光化学测定
- 批准号:
9402276 - 财政年份:2017
- 资助金额:
$ 146.02万 - 项目类别:
Photochemical determination of sodium channel voltage-dependent gating and composition
钠通道电压依赖性门控和成分的光化学测定
- 批准号:
10004154 - 财政年份:2017
- 资助金额:
$ 146.02万 - 项目类别:
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