In vitro Validation of Chimeric β-Galactosylceramidase Enzymes With Improved Enzymatic Activity and Increased Secretion

Ricca, Alessandra; Cascino, Federica; Morena, Francesco; Martino, Sabata; Gritti, Angela

doi:10.3389/fmolb.2020.00167

Cited by 5 publications

(6 citation statements)

References 70 publications

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“…Cells producing IDS‐GALC had improved secretion of enzyme, compared to GALC‐only producing cells, and similar or improved cross‐correction of in vitro twitcher cells. Furthermore, the ApoE‐GALC approach has the additional opportunity to leverage increase LDLr protein expression (and therefore increased cross‐correction capabilities) via statin pharmacotherapy (Ricca et al, 2020). In summary, while recent works have shed light on the limitations of GALC cross‐correction and the delivery of ERT across the BBB, exciting novel approaches continue to be developed to facilitate enzyme replacement in GLD and other LSDs.…”

Section: Enzyme Replacement Therapymentioning

confidence: 99%

“…While this study showed promising in vivo GALC delivery to brains of twitcher mice, functional and clinical studies were not explored. A second group recently developed chimeric GALC enzymes engineered to express unique peptide domains hypothesized to improve secretion, uptake, and transport across the BBB (Ricca, Cascino, Morena, Martino, & Gritti, 2020). In particular, GALC fusion proteins to the signal peptide of iduronate‐2‐sulfatase (IDS) or the low‐density lipoprotein receptor (LDLr)‐binding domain (from ApoE II) were generated and produced by LV‐transduced cells.…”

Section: Enzyme Replacement Therapymentioning

confidence: 99%

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Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

Feltri

Weinstock

Favret

et al. 2021

Glia

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Globoid cell leukodystrophy (GLD), also known as Krabbe disease, is a lysosomal storage disorder causing extensive demyelination in the central and peripheral nervous systems. GLD is caused by loss‐of‐function mutations in the lysosomal hydrolase, galactosylceramidase (GALC), which catabolizes the myelin sphingolipid galactosylceramide. The pathophysiology of GLD is complex and reflects the expression of GALC in a number of glial and neural cell types in both the central and peripheral nervous systems (CNS and PNS), as well as leukocytes and kidney in the periphery. Over the years, GLD has garnered a wide range of scientific and medical interests, especially as a model system to study gene therapy and novel preclinical therapeutic approaches to treat the spontaneous murine model for GLD. Here, we review recent findings in the field of Krabbe disease, with particular emphasis on novel aspects of GALC physiology, GLD pathophysiology, and therapeutic strategies.

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Section: Enzyme Replacement Therapymentioning

confidence: 99%

Section: Enzyme Replacement Therapymentioning

confidence: 99%

Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

Feltri

Weinstock

Favret

et al. 2021

Glia

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“…The chimeric GALC enzymes produced by LV-transduced cells reduce intracellular galactosylceramide (GalCer) storage and effectively cross-correct GLD murine neurons and glial cells. These findings suggest that ERT of chimeric GALC can be used by the affected CNS cells and tissues, supporting the development of novel and more effective GT approaches for GLD (Ricca et al, 2020).…”

Section: Perspectives On the Cns-targeting Therapies And Their Limitamentioning

confidence: 61%

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

Edelmann

Maegawa

2020

Front. Mol. Biosci.

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During the past decades, several therapeutic approaches have been developed and made rapidly available for many patients afflicted with lysosomal storage disorders (LSDs), inborn organelle disorders with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes. These conditions are individually rare, but, collectively, their incidence ranges from 1 in 2,315 to 7,700 live-births. Most LSDs are manifested by neurological symptoms or signs, including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. The chronic and later-onset clinical forms are at one end of the continuum spectrum and are characterized by a subtle and slow progression of neurological symptoms. Due to its inherent physiological properties, unfortunately, the blood-brain barrier (BBB) constitutes a significant obstacle for current and upcoming therapies to achieve the central nervous system (CNS) and treat neurological problems so prevalent in these conditions. To circumvent this limitation, several strategies have been developed to make the therapeutic agent achieve the CNS. This narrative will provide an overview of current therapeutic strategies under development to permeate the BBB, and address and unmet need for treatment of the progressive neurological manifestations, which are so prevalent in these inherited lysosomal disorders.

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“…For instance, chimeric GALC with the HIV Tat protein transduction domain was shown to have a 6-fold increase in cross-correction of GALC in vitro ( 151 ). More recently, GALC secretion and blood brain barrier transport was enhanced by using an alternative signal secretion peptide (iduronate-2-sulfatase) and low-density lipoprotein receptor binding domain, respectively, both in vitro and in vivo ( 35 , 152 ). In addition, it may be worthwhile to pursue alternative therapeutic strategies.…”

Section: Discussionmentioning

confidence: 99%

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

Nasir¹,

Chopra²,

Elwood³

et al. 2021

Front. Med.

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Krabbe Disease (KD) is an autosomal metabolic disorder that affects both the central and peripheral nervous systems. It is caused by a functional deficiency of the lysosomal enzyme, galactocerebrosidase (GALC), resulting in an accumulation of the toxic metabolite, psychosine. Psychosine accumulation affects many different cellular pathways, leading to severe demyelination. Although there is currently no effective therapy for Krabbe disease, recent gene therapy-based approaches in animal models have indicated a promising outlook for clinical treatment. This review highlights recent findings in the pathogenesis of Krabbe disease, and evaluates AAV-based gene therapy as a promising strategy for treating this devastating pediatric disease.

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In vitro Validation of Chimeric β-Galactosylceramidase Enzymes With Improved Enzymatic Activity and Increased Secretion

Cited by 5 publications

References 70 publications

Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

Mechanisms of demyelination and neurodegeneration in globoid cell leukodystrophy

CNS-Targeting Therapies for Lysosomal Storage Diseases: Current Advances and Challenges

Krabbe Disease: Prospects of Finding a Cure Using AAV Gene Therapy

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