Therapeutic approaches for ABCA4-associated disorders

描述(申请人提供)：ABCA4是光感受器外节盘膜中维生素A衍生物的转运体。在缺乏功能性ABCA4蛋白的情况下，维生素A醛形成过量的双维A加合物，沉积在视网膜色素上皮(RPE)中，引发RPE细胞死亡，导致继发性光感受器退化。ABCA4基因突变导致多种疾病，如Stargardt病(STGD)、视锥-视杆细胞营养不良(CRD)、视网膜色素变性(RP)。由于ABCA4基因突变是孟德尔视网膜疾病最常见的原因(1/20人携带ABCA4变异)，ABCA4相关病理是治疗干预的重要靶点，如本文所述。我们设计了一系列翻译研究来检验这一中心假设，即替换或增强功能失调的ABCA4蛋白的活性将有效地预防或延迟与STGD、CRD和RP相关的病理。该研究计划是遗传学家、眼科医生、分子生物学家和细胞生物学家共同努力的结果，由四个相互关联的模块组成。在第一个模块中，我们建议改进和扩大我们现有的患者和特征良好的家庭的临床和基因数据库，这些家庭的疾病是由ABCA4基因突变引起的。对模块I中积累的数据的分析将最终确定特定的患者群体和未来临床试验的标准。在模块II中，我们将开发和/或描述动物模型，并利用它们来建立和测试治疗结果衡量标准。在模块III和模块IV中，我们将使用这些资源来确定基于基因疗法或小分子药物，或其组合(S)治疗ABCA4相关疾病的最佳治疗应用。这些研究的结果将作为临床试验的平台，旨在推迟或阻止所有ABCA4相关疾病的发病或进展。建议研究的实质满足了“NEI视觉障碍治疗翻译研究计划”所述的主要目标，该计划是“...支持合作的、多学科的研究计划，专注于新的治疗方法，以恢复或预防由于视觉系统疾病造成的功能丧失...通过基因治疗、药理学方法或开发适当的传递系统...”相关性(见说明)：ABCA4相关疾病是成人早期视力丧失的最常见原因。据估计，美国受影响的人数在数万人，甚至可能是数十万人之间。目前还没有有效的治疗ABCA4相关疾病的方法。确定具体的治疗方法和时间表将为ABCA4相关疾病患者的治疗应用奠定基础，并将大大改善这种疾病的预后。

DESCRIPTION (provided by applicant): ABCA4 is the transporter of vitamin A derivatives in the outer segment disk membranes of photoreceptors. In the absence of a functional ABCA4 protein vitamin A aldehyde forms excess bisretinoid adducts that are deposited in retinal pigment epithelium (RPE) triggering RPE cell death and causing secondary photoreceptor degeneration. Mutations in the ABCA4 gene are responsible for a wide variety of disorders, such as Stargardt disease (STGD), cone-rod dystrophy (CRD), retinitis pigmentosa (RP). Since mutations in the ABCA4 gene constitute the most prevalent cause of Mendelian retinal disease (1/20 people carry an ABCA4 variant), ABCA4-associated pathology is an important target for therapeutic interventions, such as proposed here. We have designed a series of translational studies to test the central hypothesis that replacing or augmenting the activity of the dysfunctional ABCA4 protein will be effective in preventing or delaying the pathology associated with STGD, CRD, and RP. The research program, a collaborative effort among geneticists, ophthalmologists, molecular biologists and cell biologists, is organized into four interrelated Modules. In the first Module, we propose to improve and expand our existing clinical and genetic databases of patients and well-characterized families where the disease is caused by mutations in the ABCA4 gene. Analysis of data accumulated in Module I will ultimately determine specific patient groups and criteria for future clinical trials. In Module II, we will develop and/or characterize animal models and utilize them to establish and test therapeutic outcome measures. In Modules III and IV, we will use these resources to determine the best therapeutic application, based on gene therapy or small molecule drugs, or their combination(s) for treatment of ABCA4-associated diseases. The outcome of these studies will serve as a platform for clinical trials geared to delay the onset, or arrest the progression, of all ABCA4-associated disorders. The essence of the proposed studies meet the stated primary goals ofthe "NEI Translational Research Program on Therapy for Visual Disorders" which is "...to support collaborative, multidisciplinary research programs focused on new therapeutic approaches to restore or prevent the loss of function due to visual system diseases... via gene therapy, pharmacological approaches, or development of appropriate delivery systems..." RELEVANCE (See instructions): ABCA4-associated disorders are the most prevalent causes of early adult vision loss. Estimated numbers of affected individuals in the US are in the range of tens, possibly even hundreds of thousands. There are currently no effective treatments for patients with ABCA4-associated diseases. Determining the specific treatment methods and schedules would form the basis of therapeutic applications for patients with ABCA4- associated disorders and would result in a profound improvement in the prognosis of this condition.