Banford Samantha, McCorvie Thomas J, Pey Angel L, Timson David J
South Eastern Health and Social Care Trust, Downpatrick BT30 6RL, UK.
Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
J Pers Med. 2021 Feb 7;11(2):106. doi: 10.3390/jpm11020106.
Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.
半乳糖血症是一种罕见的遗传性代谢疾病，由编码参与半乳糖代谢的酶的四个基因发生突变所致。目前的治疗方法是从饮食中去除半乳糖，但并不充分。因此，许多患者终身遭受身体和认知残疾。其表型从几乎无症状到危及生命的残疾不等。该疾病的根本生化原因是由于受影响的蛋白质无法正确折叠和/或发挥功能，导致酶活性降低。已经提出了许多治疗半乳糖血症的新疗法。通常，这些疗法旨在治疗症状而非根本病因。药理学伴侣（PC，即纠正错误折叠蛋白质折叠的小分子）是一种令人兴奋的半乳糖血症潜在治疗方法。理论上，它们可以恢复酶的功能，从而预防下游病理后果。实际上，尚未发现可用于半乳糖血症的药理学伴侣。在此，我们综述该疾病的生化基础，确定应用药理学伴侣的机会，并描述如何发现这些药理学伴侣。我们将通过考虑一些会影响药理学伴侣未来用于治疗半乳糖血症的临床问题来得出结论。
