Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease

Grosso, Ambra Del; Galliani, Marianna; Angella, Lucia; Santi, Melissa; Tonazzini, Ilaria; Parlanti, Gabriele; Signore, Giovanni; Cecchini, Marco

doi:10.1126/sciadv.aax7462

Cited by 49 publications

(56 citation statements)

References 44 publications

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“…This has been observed, e.g., in the case of Gaucher disease [104]. In some cases, the properties of the recombinant enzyme may be improved by chemical modifications, such as PEGylation, as has been shown for phenylalanine ammonia lyase in phenylketonuria [105], or by packing the recombinant enzyme into carriers, such as nanoparticles [106,107].…”

Section: Further Potential Therapy Optionsmentioning

confidence: 90%

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Didiášová

Banning

Brennenstuhl

et al. 2020

Cells

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Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degrees of mental retardation, autism, ataxia, and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved curative therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials, and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs, and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between researchers and patients.

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Section: Further Potential Therapy Optionsmentioning

confidence: 90%

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Didiášová

Banning

Brennenstuhl

et al. 2020

Cells

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“…The samples were mixed with Laemmli buffer containing β-mercapto-ethanol (5% final concentration), boiled for 5 min, and used for gel electrophoresis (or kept at −80 °C). Brain lysates (60 µg/lane) were processed by immunoblot, as in [ 26 , 36 ]. Briefly, samples were resolved by gel electrophoresis (SDS-PAGE) using Gel Criterion XT-Precast polyacrylamide gel 4–12% Bis-Tris (Bio-Rad, Hercules, CA, USA), transferred to nitrocellulose membranes, and probed overnight at 4 °C with primary antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…Brain and optic nerve lysates were used also to measure GALC activity in WT and TWI mice, as reported in [ 26 ]. Results were expressed in unit per microgram ((U/ug) = unit of enzyme per microgram of cell lysate; unit (U) = amount of enzyme that catalyzes 1 nmol of substrate per hour) and reported in percentage of the activity of the WT-early.…”

Section: Methodsmentioning

confidence: 99%

“…The TWI mouse presents an autosomal recessive mutation in the GALC gene with no counterpart in humans [ 23 ], and pathological phenotype closely recapitulates human pathology [ 24 , 25 ]. TWI mice are the most used animal model for the testing of experimental therapies for KD, such as enzyme replacement therapies or gene therapy [ 26 , 27 ]. With the disease progression animals experience severe tremors, paralysis of hind legs and neck muscles, important weight loss, and demyelization, and lifespan rarely extends beyond PND40 [ 9 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

et al. 2020

Self Cite

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Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule. Here, we describe morphological and functional alterations in the visual system of the Twitcher (TWI) mouse, the most used animal model of Krabbe disease. We report in vivo electrophysiological recordings showing defective basic functional properties of the TWI primary visual cortex. In particular, we demonstrate a reduced visual acuity and contrast sensitivity, and a delayed visual response. Specific neuropathological alterations are present in the TWI visual cortex, with reduced myelination, increased astrogliosis and microglia activation, and around the whole brain. Finally, we quantify PSY content in the brain and optic nerves by high-pressure liquid chromatography-mass spectrometry methods. An increasing PSY accumulation with time, the characteristic hallmark of KD, is found in both districts. These results represent the first complete characterization of the TWI visual system. Our data set a baseline for an easy testing of potential therapies for this district, which is also dramatically affected in KD patients.

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“…in the case of Gaucher disease [90]. In some cases, the properties of the recombinant enzyme may be improved by chemical modifications such as PEGylation, as has been shown for phenylalanine ammonia lyase in phenylketonuria [91], or by packing the recombinant enzyme into carriers such as nanoparticles [92,93].…”

Section: Enzyme Replacement Therapy: Special Requirements For Ssadh-dmentioning

confidence: 99%

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Didiášová¹,

Banning²,

Brennenstuhl³

et al. 2020

Preprint

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Succinic semialdehyde dehydrogenase deficiency (SSADH-D) is a genetic disorder that results from the aberrant metabolism of the neurotransmitter γ-amino butyric acid (GABA). The disease is caused by the impaired activity of the mitochondrial enzyme succinic semialdehyde dehydrogenase. SSADH-D manifests as varying degree of mental retardation, autism, ataxia and epileptic seizures, but the clinical picture is highly heterogeneous. So far, there is no approved therapy for this disease. In this review, we briefly summarize the molecular genetics of SSADH-D, the past and ongoing clinical trials and the emerging features of the molecular pathogenesis, including redox imbalance and mitochondrial dysfunction. The main aim of this review is to discuss the potential use of further therapy approaches that have so far not been tested in SSADH-D, such as pharmacological chaperones, read-through drugs and gene therapy. Special attention will also be paid to elucidating the role of patient advocacy organizations in facilitating research and in the communication between the researchers and the patients.

show abstract

Brain-targeted enzyme-loaded nanoparticles: A breach through the blood-brain barrier for enzyme replacement therapy in Krabbe disease

Cited by 49 publications

References 44 publications

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

Succinic Semialdehyde Dehydrogenase Deficiency: An Update

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