MECHANISMS OF PATHOLOGY AND NEW THERAPEUTIC OPTIONS FOR GAUCHER DISEASE AND OTHER LIPIDOSES

鞘磷脂疾病是45种以上遗传性疾病的一个亚群，统称为溶酶体储存障碍(LSD)。由于缺少参与鞘脂(脂肪)分解的特定酶或蛋白质，这种物质在受影响的细胞中积累。这些疾病会影响到肝、脾、肾、骨和中枢神经系统。高谢病是鞘脂肪病的原型，在这个项目中，我们将使用这种疾病作为这组疾病的模型。高谢病在LSD中最为流行，发病率为1：56，00新生儿，全世界每年约有2300名新生儿患病。高谢病的酶替代疗法(ERT)在治疗非神经性形式的疾病方面取得了成功。然而，ERT很昂贵(200,000-400,000美元)。大约有50名澳大利亚患者正在接受ERT，每年的费用至少为1000万美元。然而，由于治疗费用高昂，许多人没有资格接受ERT，尽管他们有严重的医疗问题。在世界范围内，目前大约有4000人接受高谢病的ERT，总药费超过每年10亿美元。然而，根据出生率和预期寿命，世界上有超过8万名高雪病患者。以目前的ERT费用来看，其中90%以上的人可能永远不会得到ERT。如果要为大多数受影响的人提供治疗，将需要更便宜的替代方案。在这个项目中，我们将使用高谢病的细胞模型来研究导致这种疾病的过程，并为这种疾病和其他类型的鞘脂样变性开发替代的、更便宜的治疗方法，目前还没有治疗方法。

The sphingolipidoses are a subgroup of the more than 45 genetic disorders known collectively as lysosomal storage disorders (LSD). As a result of the deficiency of specific enzymes or proteins involved in the breakdown of sphingolipids (fats), there is an accumulation of this material in affected cells. These diseases can affect liver, spleen, kidney, bone and the central nervous system. Gaucher disease is the prototype for the sphingolipidoses and, in this project, we will use this disease as a model for this group of disorders. Gaucher disease in the most prevalent LSD with an incidence of 1:56,00 births, worldwide there are approximately 2300 affected individuals born each year. Enzyme replacement therapy (ERT) for Gaucher disease has been successful in the treatment of the non-neuropathic form of the disease. However ERT is expensive ($200,000-400,000 pa). There are approximately 50 Australian patients undergoing ERT at a cost of at least $10 million per annum. However, due to the high cost of treatment, many people do not qualify for ERT, despite having serious medical problems. Worldwide, there are approximately 4000 people currently receiving ERT for Gaucher disease at a total drug cost of over $1.0 billion pa. However, based on birth rates and life expectancies there are over 80,000 Gaucher patients in the world. With the current cost of ERT it is likely that over 90% of these will never receive ERT. If therapy is to be made available for the majority of affected individuals, cheaper alternatives will be required. In this project we will use cellular models of Gaucher disease to study the processes leading to the disease and to develop alternative, cheaper therapies for this disease and other types of sphingolipidoses, for which no therapies currently exist.