Orphan drugs in development for urea cycle disorders: current perspectives

Figures & data

Figure 1 Enzymes and transporters of the urea cycle.

Notes: The urea cycle is shown as it is present in mitochondrion and cytosol. The encircled plus sign indicates stimulation of CPS1 by NAG. Adapted from Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. © 2012 Häberle et al.; licensee BioMed Central Ltd. Available from http://www.ojrd.com/content/7/1/32#.¹¹
Abbreviations: ARG1, arginase 1; ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; citrin, mitochondrial aspartate–glutamate antiporter; CPS1, carbamoylphosphate synthetase 1; GDH, glutamate dehydrogenase; GLNase, glutaminase; NAG, N-acetylglutamate; NAGS, N-acetylglutamate synthase; OTC, ornithine transcarbamylase; ORNT1, mitochondrial ornithine transporter.

Table 1 Potential neuroprotective agents

Agent	Proposed mechanism of action
NOS inhibitors	To mitigate the ammonia-induced upregulation of NO^Citation54
Creatine	To treat cerebral creatine deficiency caused by low arginine levels as found in all enzymatic defects of the urea cycle (except AR1 deficiency), to treat ammonia-induced cerebral energy deficits, and to protect axonal growth^Citation55-Citation57
Acetyl-L-carnitine	To treat ammonia-induced cerebral energy deficits^Citation58
Inhibition of CDK5/p25	To protect neurons from ammonia-induced death^Citation59
CNTF	To protect oligodendrocytes from ammonia neurotoxicity^Citation60
MAPK inhibitors	To inhibit the ammonia-induced activation of the MAPK pathway^Citation60,Citation61
GS inhibitors	Inhibition of brain GS will reduce glutamine accumulation in astrocytes, hereby limiting osmotic cerebral edema^Citation62,Citation63

Abbreviations: CDK, cyclin-dependent kinase; CNTF, ciliary neurotrophic factor; GS, glutamine synthetase; MAPK, mitogen-activated protein kinase; NOS, nitric oxide synthase.

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