Fetal gene therapy for neurodegenerative lysosomal storage diseases

Baruteau, Julien; Waddington, Simon

doi:10.1002/jimd.12018

Cited by 5 publications

(4 citation statements)

References 31 publications

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“…Successful experiences with LT in classic MSUD are largely available, allowing dietary liberalization, prevention of metabolic decompensations, and improved quality of life in patients and caregivers (16). Similar benefits were reported after timely LT in classic MMA and ASA, although in smaller populations, revealing substantial modification of the dismal natural course of these conditions in spite of conventional medical treatment (6–8,17,18). Longitudinal biochemical monitoring after LT in MMA, ASA, and MSUD showed substantial peripheral reduction of their disease‐specific metabolites at follow‐up, although not reaching full normalization.…”

Section: Discussionsupporting

confidence: 55%

Differential Intraoperative Effect of Liver Transplant in Different Inborn Errors of Metabolism

Porta

Romagnoli

Busso

et al. 2019

J. pediatr. gastroenterol. nutr.

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Liver transplant (LT) is a therapeutic option for a growing number of inborn errors of metabolism (IEM), including some disorders not confined to the liver. Clinical advantages of LT in maple syrup urine disease (MSUD), methylmalonic acidemia (MMA), and argininosuccinic aciduria (ASA) have been reported. However, no information on the early metabolic effect of LT after portal reperfusion is available in these disorders. Here we describe the intraoperative differential metabolic outcome of LT in MSUD, MMA, and ASA. In these IEM, LT promptly cleared toxic metabolites to safe concentrations. In MSUD, leucine concentration reached physiological concentration within 12 hours after portal reperfusion. In MMA and ASA, LT allowed faster clearance of methylmalonate and argininosuccinate, respectively, both dropping by ∼90% within the first hour after portal reperfusion. The early biochemical benefits of LT in MSUD, MMA, and ASA demonstrate its immediate effectiveness in protecting patients from intercurrent metabolic decompensations.

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Section: Discussionsupporting

confidence: 55%

Differential Intraoperative Effect of Liver Transplant in Different Inborn Errors of Metabolism

Porta

Romagnoli

Busso

et al. 2019

J. pediatr. gastroenterol. nutr.

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“…As for ERT and PC described above, the use of gene therapy for THD patients would require delivery of the therapeutic agent to the brain. This would usually entail a delivery system able to cross the BBB, however, recent research efforts into utilizing gene therapy for inherited neurodegenerative disorders have used a different approach [172,173]. For example, in a mouse model of neuropathic Gaucher disease, caused by mutations in the GBA gene leading to deficient glucocerebrosidase protein, an adeno-associated virus vector was administered by fetal intercranial injection [173].…”

Section: Gene Therapymentioning

confidence: 99%

Personalized Medicine to Improve Treatment of Dopa-Responsive Dystonia—A Focus on Tyrosine Hydroxylase Deficiency

Nygaard

Szigetvari

Grindheim

et al. 2021

JPM

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Dopa-responsive dystonia (DRD) is a rare movement disorder associated with defective dopamine synthesis. This impairment may be due to the fact of a deficiency in GTP cyclohydrolase I (GTPCHI, GCH1 gene), sepiapterin reductase (SR), tyrosine hydroxylase (TH), or 6-pyruvoyl tetrahydrobiopterin synthase (PTPS) enzyme functions. Mutations in GCH1 are most frequent, whereas fewer cases have been reported for individual SR-, PTP synthase-, and TH deficiencies. Although termed DRD, a subset of patients responds poorly to L-DOPA. As this is regularly observed in severe cases of TH deficiency (THD), there is an urgent demand for more adequate or personalized treatment options. TH is a key enzyme that catalyzes the rate-limiting step in catecholamine biosynthesis, and THD patients often present with complex and variable phenotypes, which results in frequent misdiagnosis and lack of appropriate treatment. In this expert opinion review, we focus on THD pathophysiology and ongoing efforts to develop novel therapeutics for this rare disorder. We also describe how different modeling approaches can be used to improve genotype to phenotype predictions and to develop in silico testing of treatment strategies. We further discuss the current status of mathematical modeling of catecholamine synthesis and how such models can be used together with biochemical data to improve treatment of DRD patients.

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“…Proof of concept of gene therapy has been achieved in many animal models recapitulating the human phenotype of IMDs: urea cycle defects, organic acidurias, maple syrup urine disease, phenylketonuria, tyrosinaemia type 1, glycogen storage disease type Ia, long-chain fatty acid oxidation disorders, homozygous familial hypercholesterolaemia, lipoprotein lipase deficiency, primary hyperoxaluria type I, progressive familial intrahepatic cholestasis, Wilson disease ( 4 ), Pompe disease ( 88 ), Gaucher disease ( 89 ), mucopolysaccharidosis ( 90 , 91 ) and mitochondrial diseases such as mitochondrial neurogastrointestinal encephalomyopathy ( 92 ). For example, AAV vectors have successfully targeted the four most common urea cycle defects: OTC deficiency ( 93 ), citrullinaemia 1 ( 94 ), argininosuccinic aciduria ( 95 ) and arginase deficiency ( 96 ).…”

Section: Introductionmentioning

confidence: 99%