<scp>AAV</scp>‐mediated expression of galactose‐1‐phosphate uridyltransferase corrects defects of galactose metabolism in classic galactosemia patient fibroblasts

Brophy, Megan L; Stansfield, John C.; Ahn, Youngwook; Cheng, Seng H.; Murphy, John E.; Bell, Robert D.

doi:10.1002/jimd.12468

Cited by 13 publications

(9 citation statements)

References 63 publications

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“…The occurrence of these burdensome long-term health issues has raised a great interest in designing therapies that could contribute to their prevention. Several novel therapeutic approaches currently being investigated aim for the restoration of the activity of the GALT enzyme and include GALT gene therapy [ 60 , 61 , 62 ], mRNA therapy [ 63 ], and pharmacological chaperones [ 64 ]. Other potential therapies focus on influencing the cascade of events in galactosemia and include GALK1 inhibitors [ 65 , 66 ], aldose reductase inhibitors [ 67 ], and endoplasmic reticulum stress reducers [ 68 , 69 ].…”

Section: Resultsmentioning

confidence: 99%

The Importance of Neonatal Screening for Galactosemia

2022

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Galactosemia is an inborn metabolic disorder caused by a deficient activity in one of the enzymes involved in the metabolism of galactose. The first description of galactosemia in newborns dates from 1908, ever since complex research has been performed on cell and animal models to gain more insights into the molecular and clinical bases of this challenging disease. In galactosemia, the newborn appears to be born in proper health, having a window of opportunity before developing major morbidities that may even be fatal following ingestion of milk that contains galactose. Galactosemia cannot be cured, but its negative consequences on health can be avoided by establishing precocious diagnosis and treatment. All the foods that contain galactose should be eliminated from the diet when there is a suspicion of galactosemia. The neonatal screening for galactosemia can urge early diagnosis and intervention, preventing complications. All galactosemia types may be detected during the screening of newborns for this disorder. The major target is, however, galactose-1-phosphate uridyltransferase (GALT) deficiency galactosemia, which is diagnosed by applying a combination of total galactose and GALT enzyme analysis as well as, in certain programs, mutation screening. Most critically, infants who exhibit symptoms suggestive of galactosemia should undergo in-depth testing for this condition even when the newborn screening shows normal results. The decision to enroll global screening for galactosemia among the specific population still faces many challenges. In this context, the present narrative review provides an updated overview of the incidence, clinical manifestations, diagnosis, therapy, and prognosis of galactosemia, questioning under the dome of these aspects related to the disease the value of its neonatal monitoring.

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Section: Resultsmentioning

confidence: 99%

The Importance of Neonatal Screening for Galactosemia

2022

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“…The results between the two supplements seem tissue specific, where the PSPC supplementation perhaps resulted in greater improvement for the liver and ovarian function, and the MI supplementation led to greater change in the cerebellar morphology. While additional therapies are under review to treat CG, such as small molecule inhibitors [ 92 , 93 ] and gene/mRNA therapy [ 94 , 95 , 96 , 97 ], the adjunct use of natural supplements is appealing as they can be taken at home, are non-invasive, and can be stopped at any time. However, the use of these supplements in humans still requires additional study for safety and efficacy, and could be a good option for adjunct treatment for CG in the future.…”

Section: Discussionmentioning

confidence: 99%

Harnessing the Power of Purple Sweet Potato Color and Myo-Inositol to Treat Classic Galactosemia

Hagen-Lillevik

Johnson

Siddiqi

et al. 2022

IJMS

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Classic Galactosemia (CG) is a devastating inborn error of the metabolism caused by mutations in the GALT gene encoding the enzyme galactose-1 phosphate uridylyltransferase in galactose metabolism. Severe complications of CG include neurological impairments, growth restriction, cognitive delays, and, for most females, primary ovarian insufficiency. The absence of the GALT enzyme leads to an accumulation of aberrant galactose metabolites, which are assumed to be responsible for the sequelae. There is no treatment besides the restriction of dietary galactose, which does not halt the development of the complications; thus, additional treatments are sorely needed. Supplements have been used in other inborn errors of metabolism but are not part of the therapeutic regimen for CG. The goal of this study was to test two generally recognized as safe supplements (purple sweet potato color (PSPC) and myo-inositol (MI)) that may impact cellular pathways contributing to the complications in CG. Our group uses a GalT gene-trapped mouse model to study the pathophysiology in CG, which phenocopy many of the complications. Here we report the ability of PSPC to ameliorate dysregulation in the ovary, brain, and liver of our mutant mice as well as positive results of MI supplementation in the ovary and brain.

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“…Biochemical and clinical improvement was observed up to 2 months in treated rats, suggesting efficacy of gene replacement through early adulthood [ 56 ]. Restored GALT activity and protein level as well as reduced oxidative stress were also observed in fibroblasts of CG patients transduced with AAV2-CMG-hGALT [ 57 ]. Despite its potential benefit, the observed difference between liver and brain GALT activity as well as the immune response to AAV vector and genomic instability warrant further studies before gene therapy can translate into clinical practice [ 58 ].…”

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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AAV‐mediated expression of galactose‐1‐phosphate uridyltransferase corrects defects of galactose metabolism in classic galactosemia patient fibroblasts

Cited by 13 publications

References 63 publications

The Importance of Neonatal Screening for Galactosemia

The Importance of Neonatal Screening for Galactosemia

Harnessing the Power of Purple Sweet Potato Color and Myo-Inositol to Treat Classic Galactosemia

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

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