scholarly journals Treatment of Adult Metachromatic Leukodystrophy Model Mice Using Intrathecal Administration of Type 9 AAV Vector Encoding Arylsulfatase A

2021 ◽  
Author(s):  
Noriko Miyake ◽  
Koichi Miyake ◽  
Atsushi Sakai ◽  
Motoko Yamamoto ◽  
Hidenori Suzuki ◽  
...  
Keyword(s):  
Viral Vector ◽  
Metachromatic Leukodystrophy ◽  
Genetic Diseases ◽  
Immunohistochemical Analysis ◽  
Intrathecal Administration ◽  
Neurological Symptoms ◽  
Blue Staining ◽  
Alcian Blue Staining ◽  
Arylsulfatase A ◽  
Lysosomal Storage

Abstract Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by an arylsulfatase A (ASA) deficiency and characterized by severe neurological symptoms resulting from demyelination within the central and peripheral nervous systems. We investigated the feasibility and efficacy of intrathecal administration of a type 9 adeno-associated viral vector encoding ASA (AAV9/ASA) for the treatment of 6-week-old MLD model mice, which are presymptomatic, and 1-year-old mice, which exhibit neurological abnormalities. Immunohistochemical analysis following AAV9/ASA administration showed ASA expression within the brain, with highest activities in the cerebellum and olfactory bulbs. In mice treated at 1 year, alcian blue staining and quantitative analysis revealed significant decreases in stored sulfatide within the hindbrain but not forebrain. Behaviorally, mice treated at 1 year showed no improvement in their ability to traverse narrow balance beams as compared to untreated mice. By contrast, MLD mice treated at 6 weeks showed significant decreases in stored sulfatide throughout the entire brain and improved ability to traverse narrow balance beams. These findings suggest intrathecal administration of an AAV9/ASA vector is a promising approach to treating genetic diseases of the central nervous system, including MLD, though it may be essential to begin therapy before the onset of neurological symptoms.

scholarly journals Metachromatic Leucodystrophy: A Case Report

1970 ◽  
Vol 31 (2) ◽  
pp. 143-145 ◽  
Author(s):  
Subhana Karki ◽  
Ganesh Kumar Rai ◽  
Raju Kafle
Keyword(s):  
Case Report ◽  
Autosomal Recessive ◽  
Metachromatic Leukodystrophy ◽  
Neurodegenerative Disorder ◽  
Neurological Symptoms ◽  
Arylsulfatase A ◽  
Live Births ◽  
Metachromatic Leucodystrophy ◽  
Deficient Activity

Metachromatic leukodystrophy (MLD) is an autosomal recessive neurodegenerative disorder characterized by deficient activity of the enzyme arylsulfatase-A. Deficiency of this enzyme results in intralysosomal storage of sphingolipid cerebroside 3-sulfates (sulfatides), which are abundant in myelin and neurons. A pathological hallmark of MLD is demyelination and neurodegeneration, causing various and ultimately lethal neurological symptoms. Its frequency is estimated to be 1/40,000 live births. The disease encompasses three clinical subtypes: late infantile (40% of the patients with MLD), juvenile (40%), and adult (20%).   DOI: 10.3126/jnps.v31i2.4644 J Nep Paedtr Soc 2010;31(2):143-145

scholarly journals Urine sulfatides and the diagnosis of metachromatic leukodystrophy

1996 ◽  
Vol 42 (2) ◽  
pp. 232-238 ◽  
Author(s):  
M R Natowicz ◽  
E M Prence ◽  
P Chaturvedi ◽  
D S Newburg
Keyword(s):  
High Frequency ◽  
Metachromatic Leukodystrophy ◽  
Late Onset ◽  
Clinical History ◽  
Exchange Chromatography ◽  
Diagnostic Tools ◽  
Arylsulfatase A ◽  
Lysosomal Storage ◽  
Improved Method

Abstract A deficiency of the lysosomal enzyme arylsulfatase A (ASA) causes the lysosomal storage disorder metachromatic leukodystrophy (MLD). The diagnosis of MLD is straightforward in cases with deficient leukocyte or fibroblast ASA activity and a typical clinical history. However, several atypical and late-onset forms of MLD have been described. The diagnosis is also complicated by the high frequency of presumably benign polymorphisms at the ASA gene locus that are associated with markedly diminished in vitro ASA activity. Additional diagnostic tools are needed in the clinically and (or) enzymatically atypical cases. Although analyses of urinary sulfatides have been reported to be helpful in the diagnosis of MLD, previously described methods are complex and incompletely characterized and validated. We developed an improved method for determining urinary sulfatides and applied it to a cohort of individuals with MLD. The sulfatides are extracted from urine, separated from glycerol-based lipids by alkaline hydrolysis, isolated by ion-exchange chromatography, and hydrolyzed to galactosylceramide, which is then perbenzoylated and quantified by HPLC. This assay provides excellent resolution of sulfatides from other lipids and good analytical precision. In addition, the urinary sulfatide concentrations of healthy controls (mean +offSD: 0.16 +/- 0.07 nmol/mg creatinine; range: 0.07-0.34; n = 18) are clearly distinguished from those of individuals with MLD (7.6 +/- 6.1 nmol/mg creatine; 1.2-24.2; n = 20).

New Advanced Strategies for the Treatment of Lysosomal Diseases Affecting the Central Nervous System

2019 ◽  
Vol 25 (17) ◽  
pp. 1933-1950 ◽  
Author(s):  
Maria R. Gigliobianco ◽  
Piera Di Martino ◽  
Siyuan Deng ◽  
Cristina Casadidio ◽  
Roberta Censi
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Polymeric Nanoparticles ◽  
Genetic Diseases ◽  
Point Of View ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Lysosomal Diseases ◽  
The Central Nervous System ◽  
Enzyme Delivery

Lysosomal Storage Disorders (LSDs), also known as lysosomal diseases (LDs) are a group of serious genetic diseases characterized by not only the accumulation of non-catabolized compounds in the lysosomes due to the deficiency of specific enzymes which usually eliminate these compounds, but also by trafficking, calcium changes and acidification. LDs mainly affect the central nervous system (CNS), which is difficult to reach for drugs and biological molecules due to the presence of the blood-brain barrier (BBB). While some therapies have proven highly effective in treating peripheral disorders in LD patients, they fail to overcome the BBB. Researchers have developed many strategies to circumvent this problem, for example, by creating carriers for enzyme delivery, which improve the enzyme’s half-life and the overexpression of receptors and transporters in the luminal or abluminal membranes of the BBB. This review aims to successfully examine the strategies developed during the last decade for the treatment of LDs, which mainly affect the CNS. Among the LD treatments, enzyme-replacement therapy (ERT) and gene therapy have proven effective, while nanoparticle, fusion protein, and small molecule-based therapies seem to offer considerable promise to treat the CNS pathology. This work also analyzed the challenges of the study to design new drug delivery systems for the effective treatment of LDs. Polymeric nanoparticles and liposomes are explored from their technological point of view and for the most relevant preclinical studies showing that they are excellent choices to protect active molecules and transport them through the BBB to target specific brain substrates for the treatment of LDs.

scholarly journals Intravenous arylsulfatase A in metachromatic leukodystrophy: a phase 1/2 study

2020 ◽  
Author(s):  
Christine í Dali ◽  
Samuel Groeschel ◽  
Mihai Moldovan ◽  
Mohamed H. Farah ◽  
Ingeborg Krägeloh‐Mann ◽  
...  
Keyword(s):  
Metachromatic Leukodystrophy ◽  
Phase 1 ◽  
Arylsulfatase A

scholarly journals α-Galactosidase A Augmentation by Non-Viral Gene Therapy: Evaluation in Fabry Disease Mice

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 771
Author(s):  
Julen Rodríguez-Castejón ◽  
Ana Alarcia-Lacalle ◽  
Itziar Gómez-Aguado ◽  
Mónica Vicente-Pascual ◽  
María Ángeles Solinís Aspiazu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Fabry Disease ◽  
Viral Vector ◽  
Viral Gene ◽  
Lysosomal Storage ◽  
Wild Type ◽  
Dose Administration ◽  
Viral Gene Therapy ◽  
Liver Transaminases ◽  
Low Levels

Fabry disease (FD) is a monogenic X-linked lysosomal storage disorder caused by a deficiency in the lysosomal enzyme α-Galactosidase A (α-Gal A). It is a good candidate to be treated with gene therapy, in which moderately low levels of enzyme activity should be sufficient for clinical efficacy. In the present work we have evaluated the efficacy of a non-viral vector based on solid lipid nanoparticles (SLN) to increase α-Gal A activity in an FD mouse model after intravenous administration. The SLN-based vector incremented α-Gal A activity to about 10%, 15%, 20% and 14% of the levels of the wild-type in liver, spleen, heart and kidney, respectively. In addition, the SLN-based vector significantly increased α-Gal A activity with respect to the naked pDNA used as a control in plasma, heart and kidney. The administration of a dose per week for three weeks was more effective than a single-dose administration. Administration of the SLN-based vector did not increase liver transaminases, indicative of a lack of toxicity. Additional studies are necessary to optimize the efficacy of the system; however, these results reinforce the potential of lipid-based nanocarriers to treat FD by gene therapy.

Three Novel Mutant Arylsulfatase A Alleles Causing Metachromatic Leukodystrophy

2004 ◽  
Vol 29 (5) ◽  
pp. 933-942 ◽  
Author(s):  
Afshin Yaghootfam ◽  
Nicole Baumann ◽  
Andreas Schwarz ◽  
Volkmar Gieselmann
Keyword(s):  
Metachromatic Leukodystrophy ◽  
Arylsulfatase A

scholarly journals LARYNGOTRACHEITIS VIRUS IN CHICKENS

1967 ◽  
Vol 125 (3) ◽  
pp. 409-428 ◽  
Author(s):  
Betsy G. Bang ◽  
Frederik B. Bang
Keyword(s):  
Alcian Blue ◽  
Plasma Cells ◽  
Giant Cells ◽  
Functional Restoration ◽  
Nasal Fossa ◽  
Blue Staining ◽  
Alcian Blue Staining ◽  
Cell Nuclei ◽  
Histochemical Change ◽  
Laryngotracheitis Virus

Infectious laryngotracheitis can be produced in chickens as an experimental model of severe nonfatal rhinitis and sinusitis. Inoculated intranasally into unanesthetized baby chicks it remains limited to the nasal fossa, produces acute desquamation of all nasal epithelia, results in functional recovery of the respiratory epithelium, but leaves important residual abnormalities. From the earliest recognizable lesions through 4½ months' convalescence, the principal changes are as follows: 1. Initial lesions, or small syncytia of intranuclear "inclusions", first identifiable in the mucociliated cells of the shallowest portion of the epithelium at about 21 hr postinoculum (the inner surface of the maxillary conchal scroll). 2. Acute sloughing, (about 3 to 7 days), marked by: (a) spread of lesions from cell to cell via multinucleated "giant cells" which progressively slough and desquamate respiratory, olfactory, and sinus epithelia, epithelial neural elements and blood vessels; (b) appearance of numbers of eosinophilic leukocytes along the basement membrane at the sites of lesions just previous to sloughing; intensive infiltration of the submucosa with small lymphocytes after sloughing begins; (c) histochemical change in the intracellular mucus of the cells which comprise the syncytia: this mucus stains with Alcian blue alone when stained with AB-PAS; and (d) all cartilages of the maxillary conchae become flaccid, and the cell nuclei and matrix lose both basophilic and Alcian blue staining properties, effects which recede by about the 8th day. 3. Repair (about 8 to 21 days), marked by rapid initial spread of a sheet of epithelial cells over the infiltrated subrmucosa, appearance of numbers of plasma cells circulating in the tissues, formation of encapsulated secondary nodules, and mucosal adhesions. 4. Convalescence (about 1 to 4½ months when experiments terminated), marked by functional restoration of the mucociliary lining of the nasal fossa. However, at 4½ months eight specimens all show complete metaplasia of the olfactory organ (end nerves, supporting cells, and glands of Bowman) to mucociliated epithelium, all show abnormal formation and alignment of mucous acini, and about 50% have severe persistent sinusitis.

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