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

鞘脂增多症是超过45种遗传性疾病中的一个亚组，统称为溶酶体贮积症（LSD）。由于缺乏参与鞘脂（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。这些疾病可影响肝、脾、肾、骨和中枢神经系统。戈谢病是鞘脂增多症的原型，在这个项目中，我们将使用这种疾病作为这组疾病的模型。戈谢病在LSD中最为流行，发病率为1：56，00，全世界每年大约有2300名受影响的个体出生。戈谢病的酶替代疗法（ERT）已成功治疗非神经性形式的疾病。然而，ERT是昂贵的（200，000 - 400，000美元/年）。大约有50名澳大利亚患者接受ERT治疗，每年至少花费1000万澳元。然而，由于治疗费用高昂，许多人尽管有严重的医疗问题，但没有资格接受ERT。在全球范围内，目前约有4000人接受ERT治疗戈谢病，总药物费用超过10亿美元。然而，根据出生率和预期寿命，世界上有超过80，000名戈谢病患者。按照目前紧急逆转录病毒治疗的费用，其中90%以上的人可能永远不会得到紧急逆转录病毒治疗。如果要为大多数受影响的个人提供治疗，就需要更便宜的替代品。在这个项目中，我们将使用戈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病开发替代的，更便宜的疗法，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.