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Control of Breathing and Pompe Disease

呼吸控制和庞贝病

基本信息

批准号：
10615651
负责人：
BARRY J BYRNE
金额：
$ 59.32万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-15 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615651
关键词：
Address Adult Age Animal Model Antibodies Brain Breathing CRISPR/Cas technology Cardiac Central Nervous System Cerebrospinal Fluid Cessation of life Child Creatine Kinase Data Dependovirus Desmin Disease Disease Progression Dose Early treatment Enzymes Failure Gene Mutation Genes Glucan 1,4-alpha-Glucosidase Glycogen Glycogen storage disease type II Goals Grant Heart failure Human Immune Immune response Immunosuppression Impairment Injections Intravenous Laboratories Late-Onset Disorder Life Longevity Mediating Modeling Mus Muscle Mutation Myocardium Neonatal Nerve Degeneration Nervous System Neuromuscular Diseases Neurons Onset of illness Pathology Patients Phase I/II Clinical Trial Phenotype Proteins Rattus Recombinants Residual state Respiration Respiratory Diaphragm Respiratory Failure Respiratory Insufficiency Serotyping Skeletal Muscle Spinal Cord Symptoms Synapsins Testing Therapeutic Tissues Transgenes Treatment Efficacy Work autosome early onset enzyme replacement therapy enzyme therapy gallium arsenide gene product gene therapy heart function heart preservation life-sustaining therapy male mortality neural neuron loss neuropathology pediatric cardiologist postnatal pre-clinical preclinical development preservation prevent promoter rat genome respiratory response standard of care vector

项目摘要

Project Summary / Abstract: Pompe disease results from mutations in the gene for acid α-glucosidase (GAA) – an enzyme necessary to degrade lysosomal glycogen. Early-onset disease occurs in the absence of functional GAA which leads to cardiorespiratory failure early in life. Late-onset disease is associated with reduced GAA activity and gradual progression to respiratory failure. Work from our first two grant cycles indicates neural involvement in respiratory failure in Gaa-/- mice and Pompe patients. This is relevant since the standard of care – intravenous enzyme therapy using recombinant GAA - does not reach the central nervous system (CNS) and patients still progress to respiratory failure. Our overarching hypothesis is that adeno-associated virus (AAV) therapy is capable of restoring life-long GAA expression throughout the CNS, skeletal and cardiac muscle, thereby preserving cardiorespiratory function and prolonging life. Aim 1 focuses on AAV therapy for early-onset disease which requires early life treatments that can prevent both respiratory and cardiac failure. To better study this problem, we created a Gaa null (Gaa-/-) rat model which recapitulates the early onset phenotype with cardiorespiratory pathology and early mortality. Preliminary data indicate that neonatal AAV-GAA therapy (desmin promoter, AAV9 serotype) evokes no detectable immune response, mitigates cardiac and respiratory pathology and prevents early death. Thus, we hypothesize that a single intravenous AAV-GAA dose in young rats can drive persistent and widespread GAA expression and extend the Pompe rat lifespan. Aim 2 addresses late onset Pompe disease in which respiratory failure is the primary cause of mortality. Based on data from our first two grant cycles we hypothesize that neural directed AAV-GAA therapy in adult Pompe rats is sufficient to prevent respiratory decline and extend the lifespan. By packaging AAV-GAA with muscle (creatine kinase 8), neural (synapsin) or tissue specific (muscle and neural, desmin) promoters, and delivering the vector intrathecally, intravenously, or both, we can drive GAA expression in a manner that will determine if neural correction is necessary and sufficient to prevent decline. The aforementioned Gaa null rat will be used to test proof-of-concept for neural vs. muscle correction in the absence of endogenous GAA activity. We will also use another new Pompe rat model in which CRISPR/cas9 has been used to insert the most common human gene mutation causing late-onset Pompe disease (IVS1) into the rat genome. This is important because the IVS1 mutation leads to low but not absent GAA activity and is associated with delayed progression to respiratory failure. The proposed work is significant because current therapeutic strategies in Pompe disease only delay disease progression with eventual respiratory failure. The strategies proposed here will also contribute to the broader goal of advancing gene therapy for neurodegenerative conditions and autosomal recessive diseases.

项目摘要/摘要：庞贝病是由酸性α-葡萄糖苷酶基因突变引起的--这是一种必需的酶降解溶酶体糖原。早发性疾病是在缺乏功能性GAA的情况下发生的，这导致生命早期的心肺衰竭。迟发性疾病与GAA活性降低和渐进性相关进展为呼吸衰竭。我们前两个赠款周期的工作表明神经参与了 GAA-/-小鼠和Pompe患者的呼吸衰竭。这是相关的，因为护理的标准-静脉注射使用重组GAA-的酶疗法无法到达中枢神经系统(CNS)，患者仍呼吸衰竭的进展。我们的主要假设是腺相关病毒(AAV)治疗能够在整个中枢、骨骼和心肌中恢复终生GAA的表达，从而保护心肺功能，延年益寿。目的1关注早发性AAV疗法这种疾病需要早期生命治疗，可以预防呼吸和心力衰竭。为了更好地为了研究这个问题，我们建立了一个GAA缺失(GAA-/-)大鼠模型，它概括了早期发病的表型心肺病理与早期死亡率。初步数据显示，新生儿AAV-GAA疗法 (Desmin启动子，AAV9血清型)不能引起可检测到的免疫反应，减轻心脏和呼吸病理和防止过早死亡。因此，我们假设年轻患者单次静脉注射AAV-GAA剂量大鼠可以驱动持续和广泛的GAA表达，并延长庞贝大鼠的寿命。目标2 解决迟发性庞培病，呼吸衰竭是导致死亡的主要原因。基于来自我们前两个资助周期的数据，我们假设神经导向的AAV-GAA治疗成年Pompe大鼠足以防止呼吸衰退，延长寿命。通过用肌肉包装AAV-GAA (肌酸激酶8)、神经(突触素)或组织特异性(肌肉和神经，结蛋白)启动子，并递送我们可以通过鞘内、静脉或两者的方式驱动GAA的表达，从而决定是否神经矫正对于防止衰退是必要的，也是充分的。将使用前述GAA空RAT 在没有内源性GAA活性的情况下，测试神经与肌肉矫正的概念验证。我们会我还使用了另一个新的Pompe大鼠模型，在该模型中，CRISPR/Cas9已被用于插入最常见的导致迟发性庞贝病(IVS1)的人类基因突变进入大鼠基因组。这事很重要因为IVS1突变导致低GAA活性，但不是缺失，并与延迟相关进展为呼吸衰竭。这项拟议的工作意义重大，因为目前的治疗策略庞贝病只会延缓疾病的进展，最终导致呼吸衰竭。这里提出的战略也将有助于推进神经退行性疾病的基因治疗这一更广泛的目标常染色体隐性遗传病。

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Altered activation of the diaphragm in late-onset Pompe disease.

DOI：
10.1016/j.resp.2015.11.013
发表时间：
2016-02-01
期刊：
Respiratory physiology & neurobiology
影响因子：
2.3
作者：
Smith BK;Corti M;Martin AD;Fuller DD;Byrne BJ
通讯作者：
Byrne BJ

Optogenetic activation of the tongue in spontaneously breathing mice.

自主呼吸小鼠舌头的光遗传学激活。

DOI：
10.1016/j.resp.2022.103998
发表时间：
2023
期刊：
Respiratory physiology & neurobiology
影响因子：
2.3
作者：
Singer,MicheleL;Benevides,EthanS;Rana,Sabhya;Sunshine,MichaelD;Martinez,RobertC;Barral,BrianE;Byrne,BarryJ;Fuller,DavidD
通讯作者：
Fuller,DavidD

Hypoxia-induced short-term potentiation of respiratory-modulated facial motor output in the rat.