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Development of PMP22 siRNA Conjugates for Treatment of Charcot-Marie-Tooth Disease Type 1A

开发用于治疗 1A 型腓骨肌萎缩症的 PMP22 siRNA 缀合物

基本信息

批准号：
10158135
负责人：
Arthur Thomas Suckow
金额：
$ 38.79万
依托单位：
DTX PHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10158135
关键词：
17p11.2 Adult Affect Anatomy Animals Antisense Oligonucleotides Atrophic Automobile Driving Biological Biological Assay Biological Markers Cells Charcot-Marie-Tooth Disease Chromosomes Clinic Clinical Coupled Data Deformity Demyelinations Development Disease Disease Outcome Disease model Distal Dose Drug Delivery Systems Evaluation Fatty Acids Foot Deformities Foundations Functional disorder Future Gene Dosage Gene Targeting Generations Genes Grant Human Hyporeflexia In Vitro Inherited Intrathecal Injections Intravenous Leg Libraries Life Liver Maintenance Measurement Mediating Messenger RNA Modality Modeling Motor Mus Muscle Muscle Weakness Muscular Atrophy Myelin Nerve Neural Conduction Neurons Neuropathy Numbness Occupational Therapy Onset of illness PMP22 gene Patients Peripheral Nerves Peripheral Nervous System Peripheral Nervous System Diseases Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Physical therapy Property Protein Overexpression Proteins Rattus Repression Risk Rodent Route Safety Schwann Cells Sensory Small Business Innovation Research Grant Small Interfering RNA Structure Technology Testing Therapeutic Thrombocytopenia Tissues Toxic effect Transfection Transgenes Transgenic Mice Treatment Efficacy United States Validation afferent nerve arm base cellular engineering cytotoxicity design efficacy study efficacy trial experimental study hereditary neuropathy improved in vivo in vivo evaluation intravenous injection kidney dysfunction knock-down mRNA Expression mouse model novel therapeutic intervention novel therapeutics overexpression protein expression remyelination sciatic nerve screening siRNA delivery skeletal therapeutic RNA therapeutic siRNA uptake

项目摘要

PROJECT SUMMARY: Charcot-Marie-Tooth (CMT) disease is the most frequent inherited neuropathy affecting the peripheral nervous system and is characterized by a group of genetically and clinically heterogeneous disorders leading to progressive weakness and atrophy in distal muscles, sensory loss, hyporeflexia and skeletal deformity. CMT type 1A (CMT1A) is the most prevalent form, affecting 1 in 10,000 people, and is associated with a 1.4-Mbp duplication in the chromosome 17p11.2 region, which contains the peripheral myelin protein 22 (PMP22) gene. PMP22 is essential for the structure, development and maintenance of peripheral nerve myelin. PMP22 overexpression prompts cycles of demyelination-remyelination resulting in dysfunction in Schwann cells. Due to the association of PMP22 gene dosage with neuropathic phenotypes, therapeutic strategies are primarily focused on repressing PMP22 overexpression. RNA therapeutics, like antisense oligonucleotides (ASO) and siRNA, are attractive because they target messenger RNA and thus can modulate the expression of protein targets inaccessible to other therapeutic modalities. Challenges identifying safe and effective ways to deliver RNA therapeutics into cells outside the liver have limited the clinical deployment of this promising therapeutic class. For instance, a recent study used an ASO to decrease PMP22 mRNA in affected nerves, improving phenotypes in rat and mouse models of CMT1A. However, very high drug doses (multiple 100 mg/kg doses) were required to see a beneficial effect. At such high doses, the risk of toxicities related to ASO treatment, such as thrombocytopenia and renal dysfunction, preclude further development. DTx Pharma has identified a fatty acid motif that when covalently coupled to siRNA/ASO results in efficient delivery to multiple cells and tissues, including sciatic nerve (relevant for CMT), resulting in potent repression of target gene mRNA expression. Herein, we propose to explore whether DTx technology can be applied to PMP22-targeting siRNAs to correct its overexpression in Schwann cells in a mouse model of CMT1A, providing strong proof of concept for designing future therapeutic efficacy studies. We will explore this in 2 aims. Aim 1 will screen a library (~36 in addition to what we’ve screened to date) of siRNA candidates targeting PMP22 in vitro using both primary human Schwann cells and HEK293 cells engineered to express human PMP22 to identify potent and non-toxic siRNAs that will be conjugated to the DTx motif and further validated in vitro. In Aim 2, the 10 most active hits from aim 1 will be dosed in two parallel studies via intravenous or intrathecal administration in C3-PMP22 mice, a model of CMT1A, to assess dosing route, safety and target engagement in the sciatic nerve and Schwann cells. The more successful dosing route will be utilized in follow-on studies to explore dose range and duration of action for suppressing PMP22 expression to wildtype levels. Data from these studies will help us understand if DTx PMP22 siRNA is a viable approach for treatment of CMT1A and provide the foundation for a phase 2 SBIR grant focused on efficacy trials in rodents, non-GLP toxicity studies and validation in higher species.

项目总结: