Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models.
Hcrtr2 mutations underlie the etiology of canine narcolepsy, deficiencies in orexin-producing neurons are observed in the human disorder, and ablation of mouse orexin neurons or the Hcrt gene results in a narcolepsy-cataplexy phenotype.
To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase.
To determine whether hypocretin receptor gene (hcrtR1 and hcrtR2) expression is affected after long-term hypocretin ligand loss in humans and animal models of narcolepsy.
By using microarray technology we have screened the expression of 29760 genes in the brains of Doberman dogs with a heritable form of narcolepsy (homozygous for the canarc-1 [HCRTR-2-2] mutation), and their unaffected heterozygous siblings.
The orexin-2/hypocretin-2 (OX2R) receptor gene is mutated in canine narcolepsy and disruption of the prepro-orexin/hypocretin ligand gene results in both an animal model of narcolepsy and sporadic cases of the human disease.
The positional cloning of the hypocretin receptor 2, the gene for autosomal recessive canine narcolepsy, has led to the development of a physical map spanning a large portion of canine chromosome 12 (CFA12), in a region corresponding to human chromosome 6p12-q13.
In this study of American and Icelandic patients with narcolepsy, the authors found no significant association between narcolepsy and single-nucleotide polymorphisms in the genes for hypocretin or its two known receptors, hypocretin receptor-1 and hypocretin receptor-2.