Monogenic and syndromic diabetes due to endoplasmic reticulum stress

Stone, Stephen; Abreu, Damien; McGill, Janet B.; Urano, Fumihiko

doi:10.1016/j.jdiacomp.2020.107618

Cited by 23 publications

(23 citation statements)

References 96 publications

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“…Childhood-onset diabetes has been described in individuals carrying WFS1 and CISD2 mutations, leading to Wolfram syndrome (1), and recessive mutations in the DNAJC3 (40) and PPP1R15B genes (41). Indeed, the MANF syndrome clinical features of diabetes, microcephaly, and other neurological features are overlapping with those seen in patients with the above mutations (33,42). Thus, homozygous MANF mutations constitute a novel form of childhood-onset diabetes caused by dysregulated ER stress, and therefore, MANF should be included in the gene panels testing for monogenic diabetes.…”

Section: Discussionmentioning

confidence: 99%

Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

et al. 2021

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Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that plays a crucial role in attenuating ER stress responses. Although MANF is indispensable for the survival and function of mouse b-cells, its precise role in human b-cell development and function is unknown. In this study, we show that lack of MANF in humans results in diabetes due to increased ER stress, leading to impaired b-cell function. We identified two patients from different families with childhood diabetes and a neurodevelopmental disorder associated with homozygous loss-of-function mutations in the MANF gene. To study the role of MANF in human b-cell development and function, we knocked out the MANF gene in human embryonic stem cells and differentiated them into pancreatic endocrine cells. Loss of MANF induced mild ER stress and impaired insulin-processing capacity of b-cells in vitro. Upon implantation to immunocompromised mice, the MANF knockout grafts presented elevated ER stress and functional failure, particularly in recipients with diabetes. By describing a new form of monogenic neurodevelopmental diabetes syndrome caused by disturbed ER function, we highlight the importance of adequate ER stress regulation for proper human b-cell function and demonstrate the crucial role of MANF in this process.

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Section: Discussionmentioning

confidence: 99%

Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

et al. 2021

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“…In order to aid with recruitment, our study team collaborated with existing natural history studies and patient organizations. Another challenge facing this study is the vast clinical heterogeneity seen in the spectrum of individuals with Wolfram syndrome (38). Independent of age, some individuals are more severely affected or progress more rapidly than others.…”

Section: Discussionmentioning

confidence: 99%

A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome

Abreu¹,

Stone²,

Pearson³

et al. 2021

JCI Insight

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Background: Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration.Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial. Methods:Based on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic -cell functions, visual acuity, quality of life measures related to vision, and neurological functions. Results:The results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Overall, -cell functions were not significantly improved by dantrolene, but there was a significant correlation between baseline -cell functions and the change in -cell responsiveness (R 2 , p=0.004) after 6 months of dantrolene therapy. Other outcome measures, including visual acuity and neurological functions, were not improved by dantrolene sodium treatment within 6 months. As previously reported, markers of inflammatory cytokines and oxidative stress, such as IFN, IL-1, TNF, and isoprostane, were elevated in subjects with Wolfram syndrome. Conclusion:This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome. Abreu & Stone et. al. 3 Trial registration ClinicalTrials.gov Identifier NCT02829268 Conflict of interest statement F. Urano received research funding from Eli Lilly, Ono Pharmaceuticals, and Amarantus BioScience for the development of MANF-based regenerative therapy for Wolfram syndrome, optic nerve atrophy, and diabetes. F. Urano received chemical compounds from Amylyx Pharmaceuticals, Mitochon Pharmaceuticals, Aetas Pharma, and National Center for Advancing Translational Sciences for the development of small molecule-based therapies for ER stress-related disorders, including Wolfram syndrome. F. Urano is an inventor of two patents related to the treatment of Wolfram syndrome, US 9,891,231 SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS and US 10,441,574 and US 10,695,324 TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS. F. Urano is a Founder and President of CURE4WOLFRAM, INC.

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“…This helped inform our decision toward an open-label phase 1b/2a design, as a positive outcome would clear a path for more widespread adoption of a drug aimed at slowing the progression of Wolfram syndrome that is at least proven to be safe, if not necessarily effective in all individuals. The final challenge facing this study is the vast clinical heterogeneity seen in the spectrum of individuals with Wolfram syndrome 31 . Independent of age, some individuals are more severely affected or progress more rapidly than others.…”

Section: Discussionmentioning

confidence: 99%

“…The final challenge facing this study is the vast clinical heterogeneity seen in the spectrum of individuals with Abreu & Stone et. al.Wolfram syndrome31 . Independent of age, some individuals are more severely affected or progress more rapidly than others.…”

mentioning

confidence: 99%

A Phase 1b/2a Clinical Trial of Dantrolene Sodium in Patients with Wolfram Syndrome

Abreu¹,

Stone²,

Pearson³

et al. 2020

Preprint

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Background. Wolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial. Methods: Based on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic beta-cell functions, visual acuity, quality of life measures related to vision, and neurological functions. Results: The results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in beta-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions. Conclusion. This study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.

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Monogenic and syndromic diabetes due to endoplasmic reticulum stress

Cited by 23 publications

References 96 publications

Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

Loss of MANF Causes Childhood-Onset Syndromic Diabetes Due to Increased Endoplasmic Reticulum Stress

A phase 1b/2a clinical trial of dantrolene sodium in patients with Wolfram syndrome

A Phase 1b/2a Clinical Trial of Dantrolene Sodium in Patients with Wolfram Syndrome

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