Galactosemia: opportunities for novel therapies

McCorvie, Thomas J.; Timson, David J.

doi:10.1016/b978-0-12-819132-3.00011-7

Cited by 4 publications

(8 citation statements)

References 188 publications

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“…Pharmacological chaperones are small molecules that bind specifically to their targets, rescuing specific variant proteins by facilitating intracellular folding and trafficking, increasing cellular stability and activity, and/or preventing premature degradation [ 4 , 21 ]. Pharmacological chaperones present advantageous features: (i) low synthesis cost; (ii) oral availability with broad biodistribution; (iii) low molecular weight that can potentially, allow them to cross the blood–brain barrier (BBB) [ 77 , 78 , 79 ].…”

Section: Potential Therapiesmentioning

confidence: 99%

“…GALK1 inhibitors were proposed as treatment strategy many years ago [ 86 ], and have been thoroughly investigated over the years. The strategy aims to reduce the accumulation of Gal-1-P in GALT deficiency, as Gal-1-P is considered a major key player in the pathogenic mechanism in classic galactosemia [ 4 , 12 , 21 ]. The milder clinical picture of type II (GALK1 deficiency) galactosemia supported this view although standardized follow-up data are currently lacking [ 87 , 88 ].…”

Section: Potential Therapiesmentioning

confidence: 99%

“…Aldose reductase (AR) inhibitors target the NADPH-dependent aldose reductase conversion of [ 2 , 21 , 61 , 96 ] galactose to galactitol, which cannot be transported across the cell membrane due to its poor diffusivity and cannot be further metabolized, leading to accumulation in cells. This leads to an osmotic phenomenon with subsequent cell swelling and ultimately apoptosis [ 97 , 98 ].…”

Section: Potential Therapiesmentioning

confidence: 99%

“…The pathogenic mechanisms underlying the acute and long-term organ-specific complications of classic galactosemia are complex and remain to be fully elucidated. Currently described contributing factors include accumulation of galactose metabolites (galactitol, galactonate and Gal-1-P) [ 2 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 ], uridine diphosphate (UDP)-hexose alterations and impaired glycosylation [ 21 , 25 , 31 , 32 , 33 , 34 , 35 , 36 ], endoplasmic reticulum (ER) stress with subsequent unfolded protein response (UPR), induction and alteration of signaling pathways [ 2 , 3 , 4 , 37 , 38 , 39 , 40 , 41 , 42 ], and oxidative stress [ 4 , 29 , 43 , 44 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Potential Therapiesmentioning

confidence: 99%

Section: Potential Therapiesmentioning

confidence: 99%

Section: Potential Therapiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Current and Future Treatments for Classic Galactosemia

Delnoy

Coelho

Rubio‐Gozalbo

2021

JPM

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“…Therefore, long-term side-effects are inevitable [ 56 , 57 , 58 ]. Treatments under investigation include GALK1 inhibitors, antioxidants, aldose reductase inhibitors, gene therapy, mRNA therapy, stress signalling pathway inhibitors and enzyme replacement therapy (recently reviewed in [ 59 , 60 , 61 , 62 , 63 ]). Another potential strategy is the use of pharmacological chaperones (PCs).…”

Section: Introductionmentioning

confidence: 99%

Galactosemia: Towards Pharmacological Chaperones

Banford

McCorvie

Pey

et al. 2021

JPM

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Galactosemia is a rare inherited metabolic disease resulting from mutations in the four genes which encode enzymes involved in the metabolism of galactose. The current therapy, the removal of galactose from the diet, is inadequate. Consequently, many patients suffer lifelong physical and cognitive disability. The phenotype varies from almost asymptomatic to life-threatening disability. The fundamental biochemical cause of the disease is a decrease in enzymatic activity due to failure of the affected protein to fold and/or function correctly. Many novel therapies have been proposed for the treatment of galactosemia. Often, these are designed to treat the symptoms and not the fundamental cause. Pharmacological chaperones (PC) (small molecules which correct the folding of misfolded proteins) represent an exciting potential therapy for galactosemia. In theory, they would restore enzyme function, thus preventing downstream pathological consequences. In practice, no PCs have been identified for potential application in galactosemia. Here, we review the biochemical basis of the disease, identify opportunities for the application of PCs and describe how these might be discovered. We will conclude by considering some of the clinical issues which will affect the future use of PCs in the treatment of galactosemia.

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Repurposing drugs for the treatment of galactosemia

Timson

2019

Expert Opinion on Orphan Drugs

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Introduction: Galactosemia describes four diseases resulting from mutations in genes which code for enzymes involved in the metabolism of galactose and its derivatives. It has a wide range of symptoms ranging from the relatively mild (early onset cataracts) to severe damage to the liver, brain and ovaries which results in significant physical and cognitive disability. The only treatment is the removal or reduction of galactose in the diet. This treatment is unsatisfactory, particularly in the most severe forms of the disease. Considerable research efforts are being made to develop specific therapies for galactosemia. These include gene therapies, pharmacological chaperones, drugs to block the production of potentially toxic metabolites and enzyme replacement therapy. However, these are unlikely to be translated into the clinic for at least a decade.Areas covered: This review considers existing drugs, nutrients and treatments which could be relatively rapidly repurposed for the treatment of galactosemia. If successful, these would enable an improvement in the prognosis for galactosemia patients. Expert opinion: Dietary antioxidants which are already widely used and generally considered safe (e.g. resveratrol, purple sweet potato colour) should be tested for their efficacy in galactosemia.Pharmaceutical antioxidants (e.g. idebenone) should also be considered. Phosphate supplementation, along with careful monitoring of phosphate levels in the patient's diet should also be considered. Efforts to develop specific therapies for galactosemia should continue.

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Galactosemia: opportunities for novel therapies

Cited by 4 publications

References 188 publications

Current and Future Treatments for Classic Galactosemia

Current and Future Treatments for Classic Galactosemia

Galactosemia: Towards Pharmacological Chaperones

Repurposing drugs for the treatment of galactosemia

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