Salubrinal enhances eIF2α phosphorylation and improves fertility in a mouse model of Classic Galactosemia

Balakrishnan, Bijina; Siddiqi, Anwer; Mella, Jessica; Lupo, A.; Li, E.; Hollien, Julie; Johnson, Joshua; Lai, Kent

doi:10.1016/j.bbadis.2019.07.010

Cited by 21 publications

(34 citation statements)

References 66 publications

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“…The drug had no detectable adverse effects on the mice, as assessed by birth weight and organ weights of treated animals [38]. The results are concordant with those reported in the academic literature by the same research group [39,40].…”

Section: Salubrinal To Reverse Defects In Pi3k/akt Signallingsupporting

confidence: 86%

Therapies for Galactosemia: a Patent Landscape

Timson

2020

Pharm. Pat. Anal.

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Galactosemia is the inherited inability to metabolise galactose. The most common results from a lack of galactose 1-phosphate uridylyltransferase activity. The current treatment, removal of galactose from the diet, is inadequate and often fails to prevent long-term complications. Since 2015, three patents have been filed describing novel therapies. These are: the use of aldose reductase inhibitors to reduce cataracts and, possibly, other symptoms; salubrinal to stimulate cellular stress responses; mRNA therapy to increase cellular galactose 1-phosphate uridylyltransferase activity. The viability of all three is supported by academic studies. The potential and drawbacks of all three are discussed and evaluated.

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Section: Salubrinal To Reverse Defects In Pi3k/akt Signallingsupporting

confidence: 86%

Therapies for Galactosemia: a Patent Landscape

Timson

2020

Pharm. Pat. Anal.

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“…In our mouse model, we see subfertility, reduced follicles, increased corpus luteum, increased ER/UPR stress markers, and decreased PI3K/AKT signaling in twomonth-old ovaries compared to wild-type ovaries (Balakrishnan, et al 2017b;Balakrishnan, et al 2019a). While there were significantly fewer primordial follicles at two months of age, follicle counts at post-natal day eight (unpublished data) showed no difference in primordial follicles when compared to wild type mice, suggesting that follicle loss occurs progressively between birth and sexual maturity in a mouse, similar to case reports in females with CG (Balakrishnan et al 2019b;Kaufman et al 1981). Recently we used Salubrinal, to modulate the UPR signaling in our GalT-deficient mouse model (Balakrishnan et al 2019a).…”

Section: Pathophysiology Of Primary Ovarian Insufficiency In Galactosemiamentioning

confidence: 59%

“…While the exact mechanism of ovarian failure is not known, overwhelming evidence suggests that excess gal-1P is the main culprit in CG POI (Balakrishnan, et al 2019b;Bandyopadhyay et al 2003a;Guerrero et al 2000;Tang, et al 2014;Thakur et al 2017;Vanoevelen, et al 2018;Yuzyuk et al 2018). Females heterozygous for pathogenic variants in GALT, and with other types of galactosemia, such as galactokinase deficiency (GALK1), do not have chronically elevated levels of gal-1P, have a normal ovarian reserve, and do not undergo menopause at a premature age (Badik, et al 2011;Knauff, et al 2007;Rubio-Gozalbo, et al 2021).…”

Section: Pathophysiology Of Primary Ovarian Insufficiency In Galactosemiamentioning

confidence: 99%

Pathophysiology and management of classic galactosemic primary ovarian insufficiency

Hagen-Lillevik

Rushing

Appiah

et al. 2021

Reproduction and Fertility

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Classic Galactosemia is an inborn error of carbohydrate metabolism associated with early-onset primary ovarian insufficiency (POI) in young women. Our understanding of the consequences of galactosemia upon fertility and fecundity of affected women is expanding, but there are important remaining gaps in our knowledge and tools for management, and a need for continued dialogue so that the special features of the condition can be better managed. Here, we review galactosemic POI and its reproductive endocrinological clinical sequelae and summarize current best clinical practices for its management. Special consideration is given to the very early-onset nature of the condition in the pediatric/adolescent patient. Afterward, we summarize our current understanding of the reproductive pathophysiology of galactosemia, including the potential action of toxic galactose metabolites upon the ovary. Our work establishing that ovarian cellular stress reminiscent of endoplasmic reticulum (ER) stress is present in a mouse model of galactosemia, as well as work by other groups, are summarized.

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“…This indicates that reduced ER stress might be of therapeutic interest for the brain and ovary, suggesting a possible role for eukaryotic initiation factor 2α (eIF2α) inhibitors that reverse the downregulated pathway in fertility preservation and neurological complications. Positive effects of the eIF2α inhibitor salubrinal have been reported in a mouse model of classic galactosemia without detectable adverse effects [ 39 , 110 ]. Moreover, a protective effect on primordial follicle loss, and an increase in fertility, was found [ 39 ].…”

Section: Potential Therapiesmentioning

confidence: 99%

Current and Future Treatments for Classic Galactosemia

Delnoy

Coelho

Rubio‐Gozalbo

2021

JPM

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Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.

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Salubrinal enhances eIF2α phosphorylation and improves fertility in a mouse model of Classic Galactosemia

Cited by 21 publications

References 66 publications

Therapies for Galactosemia: a Patent Landscape

Therapies for Galactosemia: a Patent Landscape

Pathophysiology and management of classic galactosemic primary ovarian insufficiency

Current and Future Treatments for Classic Galactosemia

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