Image_4_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_2_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpeg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_3_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpeg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_1_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpeg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_5_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Binding of D₁/D₅ specific ligand [³H]SCH23390 to hippocampal membranes of wt and <i>Wfs1</i> knockout mice.

<p>Comparison of specific binding of radioligand [³H]SCH23390 to hippocampal membranes of wt and <i>Wfs1</i> knockout mice. (A) Binding curve of [³H]SCH23390 binding to pooled samples of wt (triangle) and <i>Wfs1</i> knockout (circle) mice. The membrane suspensions (3 mg/well) were incubated with different concentrations of [³H]SCH23390 for 60 min and bound radioactivity was measured. Data are presented as mean ± SEM from experiments (n = 3) performed in duplicates. (B) The level of [³H]SCH23390 binding sites of individual wt and <i>Wfs1</i> knockout mice determined in hippocampal membrane suspensions (6.7 mg/ml.) incubated with 4 nM radioligand. Data presented as mean ± SEM of all the mice tested. *P < 0.05. Data of individual mice are presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0172825#pone.0172825.s006" target="_blank">S1 Table</a>.</p

The expression of <i>Wfs1</i> and <i>Drd1a</i> in the adult red-eared slider turtle (<i>Trachemys scripta</i>) brain.

<p>The expression of <i>Wfs1</i> and <i>Drd1a</i> in the adult red-eared slider turtle (<i>Trachemys scripta</i>) brain, shown by mRNA <i>in situ</i> hybridization on coronal brain sections. The sections are in anterio-posterior order from left to right. The probes are indicated on the left side of the figure. <i>Wfs1</i> expression is widespread in the brain of <i>T</i>.<i>scripta</i>, being distinguishedly strong in MC, DC, PT and near the ventricular surface in the caudal DVR (A-D). <i>Drd1a</i> expression occupies the same regions as that of <i>Wfs1</i>, but is missing in MC and very weak in DC and caudal DVR (E-H). Unlike <i>Wfs1</i>, <i>Drd1a</i> is present in LC (E-G). For abbreviations, see list. Scale bar is 1 mm.</p

The expression of <i>Wfs1</i> and <i>Drd1a</i> in the adult chick brain.

<p>The expression of <i>Wfs1</i> and <i>Drd1a</i> in the adult chick brain, shown by mRNA <i>in situ</i> hybridization on coronal brain sections. The section plane is shown on image L. The probes are indicated on the left side of the figure. Both, <i>Wfs1</i> and <i>Drd1a</i> show strong expression in rostral to medial MSt (A-F). In Acb and StPalAcb, the expression of <i>Wfs1</i> is substantially weaker than in the surrounding striatal structures (A-B). The expression of <i>Drd1a</i> is weak in Acb and StPalAcb, and is missing in SPO (D-F). In LSt, both <i>Wfs1</i> and <i>Drd1a</i> expression show strengthening gradient in rostrocaudal direction (A-G,J). <i>Wfs1</i>-expressing cells in PHi are shown in higher magnification (I). In the adult brain, ADo and APir are delineated with <i>Wfs1</i> expression, but remain hardly distinguishable by <i>Drd1a</i> expression (H,K). Note that GP is devoid of both <i>Drd1a</i> and <i>Wfs1</i> (B,E,G,J). For abbreviations, see list. Scale bar is 1 mm in A-H and J-K and 500 μm in I.</p

Distribution of Wfs1 protein in the striata of common quail (<i>Coturnix coturnix</i>) and red-eared slider turtle (<i>Trachemys scripta</i>) brains.

<p>Distribution of Wfs1 protein in the striata of quail (<i>Coturnix coturnix</i>) and red-eared slider turtle (<i>Trachemys scripta</i>) brains. The panel shows fluorescent immunohistochemistry on coronal brain sections. Wfs1 expression (green) is seen in medial striatum of quail (A, MSt) and turtle (D, St). Concave arrowheads point the expression in soma in both species (C, F). Wfs1 is detectable in neuronal processes of quail (C, concave arrowheads). Nuclei are counterstained with DAPI (blue). Scale bar is 100 μm.</p

Wfs1 is expressed in dopaminoceptive regions of the amniote brain and modulates levels of D1-like receptors - Sheet 0

<p>Wfs1 is expressed in dopaminoceptive regions of the amniote brain and modulates levels of D1-like receptors</p> - Sheet