Triplex-mediated DNA repair as a novel therapy for Hurler Syndrome patients

三重介导的 DNA 修复作为 Hurler 综合征患者的新型疗法

基本信息

批准号：
8454945
负责人：
Elizabeth Peterson-Roth
金额：
$ 26.82万
依托单位：
L2 DIAGNOSTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8454945
关键词：
Address Affect Allogenic Autologous Back Binding Blood Blood - brain barrier anatomy CD34 gene Caucasians Caucasoid Race Cell Therapy Cells Clinical Clinical Research Collection DNA DNA Repair Deterioration Development Diagnostic Disease Enzymes Fabry Disease Frequencies Gaucher Disease Gene Mutation Gene Targeting Gene-Modified Genes Genetic Genetic Recombination Genome Harvest Health Personnel Hematologist Hematopoietic Stem Cell Transplantation Hereditary Disease Hospital Formularies Hospitals Human Immune Inborn Errors of Metabolism Incidence L-Iduronidase Laboratories Letters Live Birth Lysosomal Storage Diseases Marketing Mediating Modification Morbidity - disease rate Mucopolysaccharidosis I H Multiple Organ Failure Mus Mutation Neuraxis Neurologic Nonsense Mutation Oligonucleotides Patients Peptide Nucleic Acids Pharmacologic Substance Phase Physiological Process Proteins Protocols documentation Qualifying Recombinant Proteins Specialist Stem cells Supportive care Symptoms Technology Testing Therapeutic TimeLine Transplantation United States Vial device Viral Vector Work cost design disease-causing mutation effective therapy enzyme replacement therapy genetic element in vivo monocyte mortality novel phase 1 study repaired success sugar therapeutic gene

项目摘要

DESCRIPTION (provided by applicant): This is a proposal to test the feasibility of using triplex molecules for use as a therapeutic to correct Hurler Syndrome (HS). Lysosomal storage diseases (LSDs), such as HS, represent a diverse collection of monogenic disorders that have devastating clinical features. LSDs are caused by mutations in genes that encode lysosomal enzymes and other proteins that are critical for lysosomal function. HS is caused by mutations in the ¿ -L-iduronidase gene (IDUA). For many LSDs, treatment consists of enzyme replacement therapy and supportive care. However, enzyme replacement therapy costs from $90,000 to $565,000 per patient. Alternatively, allogeneic hematopoietic stem cell transplantation (HSCT) represents a highly effective treatment. However, allogeneic HSCT requires an HLA-matched donor, is associated with significant morbidity and mortality and is expensive, about $200,000 per patient. Genetic modification of autologous HSCT, using CD34+ cells, is emerging as a viable therapeutic alternative to allogeneic HSCT. Autologous HSCT is preferred because it is far less expensive and safer than allogeneic HSCT. One emerging approach to targeted genome modification in CD34+ cells is the use of triplex molecules, either in the form of triplex-forming oligonucleotides or peptide nucleic acids. These molecules bind to duplex DNA in a sequence-specific manner and stimulate recombination when combined with donor DNA molecules. Gene modification occurs via recruitment of the cells own DNA repair machinery, without the need for viral vectors. Viral vectors have proven problematic in such therapies. Our Specific Aim is to test the feasibility of using triplex molecules to correct one of the most prominent gene mutations in the IDUA gene, W402X. For this technology to be viable as a commercial therapy, we must demonstrate that we can achieve a success rate of at least 3% for correction of our gene target in CD34+ cells. Next, we must demonstrate that we can generate a sufficient number of monocytes from these stem cells to be utilized as part of a bridging therapy to wholesale HSCT. In Phase II, we will carry out in vivo studies to demonstrate in vivo efficacy and work on developmental and IND enabling studies to move this technology toward clinical studies. PUBLIC HEALTH RELEVANCE: Hurler Syndrome (HS), a devastating genetic disease that results in multiple organ failure with progressive deterioration in the central nervous system, is caused by mutations in a single gene that is involved in the processing of large sugar molecules within compartments in our cells. L2 Diagnostics LLC is proposing to develop a therapeutic gene targeting protocol to correct one of the most prominent mutations responsible for HS. Our protocol would repair this mutation in isolated blood stem cells from HS patients and then reintroduce the corrected cells back into the patient with the potential of having a significant impact on the symptoms of the disease.

描述（由申请人提供）：这是一项测试使用三链体分子作为治疗方法来纠正 Hurler 综合征 (HS) 的可行性的提案。溶酶体贮积症 (LSD)，例如 HS，代表了多种单基因疾病。具有破坏性临床特征的LSD是由编码溶酶体酶和其他对溶酶体功能至关重要的蛋白质的突变引起的。对于许多LSD，治疗包括酶替代疗法和支持治疗，但是，酶替代疗法的费用为每位患者90,000 美元至565,000 美元，另外，同种异体造血干细胞移植（HSCT）也是一种非常有效的治疗方法。然而，同种异体 HSCT 需要 HLA 匹配的供体，与显着的发病率和死亡率相关，并且费用昂贵。每名患者 200,000 美元。使用 CD34+ 细胞进行自体 HSCT 的基因改造正在成为同种异体 HSCT 的可行治疗替代方案，因为它比同种异体 HSCT 便宜得多且安全。细胞的使用是三链体分子的使用，无论是形成三链体的寡核苷酸还是肽核酸的形式，这些分子与双链体DNA结合。以序列特异性方式与供体 DNA 分子结合时，通过招募细胞自身的 DNA 修复机制来刺激重组，而无需病毒载体，我们的具体目标是测试使用三链体分子纠正 IDUA 基因中最显着的基因突变之一 W402X 的可行性。为了使这项技术成为可行的商业疗法，我们必须证明我们可以实现至少 3% 的成功率。修正我们的基因目标接下来，我们必须证明我们可以从这些干细胞中产生足够数量的单核细胞，以用作大规模 HSCT 的桥接疗法的一部分。在第二阶段，我们将进行体内研究以证明体内。功效以及开发和 IND 方面的工作使研究能够将该技术推向临床研究。公共卫生相关性：赫勒综合症 (HS) 是一种毁灭性的遗传性疾病，可导致多器官衰竭并导致中枢神经系统进行性恶化，是由参与细胞内大糖分子加工的单个基因突变引起的。我们的细胞 L2 Diagnostics LLC 正在提议开发一种治疗性基因靶向方案，以纠正导致 HS 的最显着的突变之一，我们的方案将修复从 HS 患者分离的血液干细胞中的这种突变，然后重新引入该突变。纠正后的细胞返回患者体内，有可能对疾病症状产生重大影响。