Evaluation of a Melanocortin-4 Receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency

$\textbf{Objective:}$ Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1e5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. $\textbf{Methods:}$ We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants. $\textbf{Results:}$ In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls. $\textbf{Conclusions:}$ Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.This work was supported by the Wellcome Trust (I.S.F.), the National Institute for Health Research Cambridge Biomedical Research Centre (S.O’R., I.S.F.), the Bernard Wolfe Health Neuroscience Fund (I.S.F.), the European Research Council (I.S.F.), and the Swiss National Science Foundation (PBLAP3-145870, P3SMP3-155318, PZ00P3-167826 to T.-H.C.). Funds were also obtained from the Clinical Research Programs on Obesity (Assistance Publique-Hôpitaux de Paris, and the Direction of Clinical Research (CRC) (PHRC 02076 to K.C.), as well as the Institut Benjamin Delessert and the Fondation pour la Recherche Médicale and the National Agency of Research (program “Investissements d’Avenir” with the reference ANR-10-IAHU-05). The clinical trial was supported by Rhythm Pharmaceuticals

DNA rearrangements linked to expression of a predominant surface antigen gene of trypanosomes.

African trypanosomes show an extensive capacity for antigenic variation. The serotype of each antigenic variant is determined by a variant-specific surface antigen (VSA) which forms a continuous coat over the entire surface of the parasite. All known VSAs are glycoproteins whose antigenic specificity is associated with the protein moiety. The expression of some of the VSA genes is linked to the duplication of a 'basic' copy (BC) of the gene and to the transposition of the additional or 'expression-linked' copy (ELC) to a new site, where it is transcribed. Other VSA genes seem to be expressed without being duplicated; they are, however, subject to rearrangements apparently unrelated to their expression. In chronic infections, different variable antigen types (VATs) tend to appear in a loosely ordered sequence: indeed, after either syringe passage or cyclical transmission through the tsetse fly, the same VATs always appear in the early stage of the disease and are therefore known as early or predominant ones. To check whether genes coding for predominant VATs can be characterized by some particular feature of their DNA sequence or gene rearrangement, we have studied here the gene coding for AnTat 1.3, which is the most predominant VAT of our Trypanosoma brucei brucei stock. Three points emerged: (1) when expressed, the AnTat 1.3 gene is duplicated and the ELC transposed in an expression site identical to the one described previously for other VSA genes; (2) its BC is located near the end of a DNA molecule, in a region which is very similar to the expression site and undergoes frequent insertions/deletions unlinked to VSA gene expression; (3) this gene does not belong to a multigene family.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: NotDefined.jinfo:eu-repo/semantics/publishe

The Trypanosoma cruzi Genome Project: Nuclear Karyotype and Gene Mapping of Clone CL Brener

By using improved pulsed field gel electrophoresis conditions, the molecular karyotype of the reference clone CL Brener selected for Trypanosoma cruzi genome project was established. A total of 20 uniform chromosomal bands ranging in size from 0.45 to 3.5 Megabase pairs (Mbp) were resolved in a single run. The weighted sum of the chromosomal bands was approximately 87 Mbp. Chromoblots were hybridized with 39 different homologous probes, 13 of which identified single chromosomes. Several markers showed linkage and four different linkage groups were identified, each comprising two markers. Densitometric analysis suggests that most of the chromosomal bands contain two or more chromosomes representing either homologous chromosomes and/or heterologous chromosomes with similar size