Therapies for Galactosemia: a Patent Landscape

Timson, David J.

doi:10.4155/ppa-2020-0004

Cited by 9 publications

(11 citation statements)

References 54 publications

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“…AR inhibitors target galactose conversion to galactitol, which accumulates in cells leading to cell swelling and apoptosis in CG [ 68 ]. Particularly, accumulation of galactitol within the lens causes galactosemic cataracts [ 69 ].…”

Section: Treatmentmentioning

confidence: 99%

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

et al. 2022

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Galactosemia is an inborn disorder of carbohydrate metabolism characterized by the inability to metabolize galactose, a sugar contained in milk (the main source of nourishment for infants), and convert it into glucose, the sugar used by the body as the primary source of energy. Galactosemia is an autosomal recessive genetic disease that can be diagnosed at birth, even in the absence of symptoms, with newborn screening by assessing the level of galactose and the GALT enzyme activity, as GALT defect constitutes the most frequent cause of galactosemia. Currently, galactosemia cannot be cured, but only treated by means of a diet with a reduced content of galactose and lactose. Although the diet is able to reverse the neonatal clinical picture, it does not prevent the development of long-term complications. This review provides an overview of galactose metabolism, molecular genetics, newborn screening and therapy of galactosemia. Novel treatments for galactosemia currently being investigated in (pre)clinical studies and potentially able to prevent long-term complications are also presented.

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Section: Treatmentmentioning

confidence: 99%

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

et al. 2022

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“…Exogenous, intracellular delivery of mRNA is emerging as a new class of medicine [59][60][61][62]. Recent advances in mRNA technology have led to improvements in stability and translation by codon optimization and encapsulation within biodegradable delivery systems, preserving mRNA integrity and allowing targeted intracellular delivery [59][60][61][62][63][64][65][66][67][68][69][70]. The required repeated dosing of this therapeutic modality tends to raise concerns about immunogenicity and therapy burden for the patients.…”

Section: Mrna Therapymentioning

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: Aldose Reductase (Ar) Inhibitorsmentioning

confidence: 99%

“…The high expression of aldose reductase in the epithelial cells of the lens leads to the formation of galactosemic cataracts [88,99]. Galactitol involvement in cognitive and neurological symptoms has been suggested [61,100]. Pseudotumor cerebri, or elevated intracranial pressure, has also been reported and is postulated to be the result of accumulation of galactitol in the brain cells leading to cerebral edema [101,102].…”

Section: Aldose Reductase (Ar) Inhibitorsmentioning

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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“…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: Figurementioning

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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Therapies for Galactosemia: a Patent Landscape

Cited by 9 publications

References 54 publications

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

Galactosemia: Biochemistry, Molecular Genetics, Newborn Screening, and Treatment

Current and Future Treatments for Classic Galactosemia

Galactosemia: Towards Pharmacological Chaperones

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