scholarly journals White Matter Pathology as a Barrier to Gangliosidosis Gene Therapy

2021 ◽  
Vol 15 ◽  
Author(s):  
Anne S. Maguire ◽  
Douglas R. Martin
Keyword(s):  
Gene Therapy ◽  
White Matter ◽  
Lysosomal Storage Diseases ◽  
Evidence Based ◽  
Lysosomal Storage ◽  
Research Groups ◽  
Myelin Sheaths ◽  
Secondary Demyelination ◽  
White Matter Pathology

The gangliosidoses are a family of neurodegenerative lysosomal storage diseases that have recently seen promising advances in gene therapy. White matter deficits are well established components of gangliosidosis pathology that are now receiving more attention because they are partially refractory to correction by gene therapy. After a brief synopsis of normal myelinogenesis, this review outlines current viewpoints on the origin of white matter deficits in the gangliosidoses and potential obstacles to treating them effectively by gene therapy. Dysmyelinogenesis (failure of myelin sheaths to form properly) is proposed as the predominant contributor to white matter pathology, but precise mechanistic details are not well understood. The involvement of neuronal storage deficits may extend beyond secondary demyelination (destruction of myelin due to axonal loss) and contribute to dysmyelinogenesis. Preclinical studies in animal models of the gangliosidoses have substantially improved lifespan and quality of life, leading to the initiation of several clinical trials. However, improvement of white matter pathology has lagged behind other metrics and few evidence-based explanations have been proposed to date. Research groups in the field are encouraged to include myelin-specific investigations in future gene therapy work to address this gap in knowledge.

Clinical Development of Cell Therapies to Halt Lysosomal Storage Diseases: Results and Lessons Learned

2021 ◽  
Vol 21 ◽  
Author(s):  
Valeria Graceffa
Keyword(s):  
Stem Cells ◽  
Gene Therapy ◽  
Ex Vivo ◽  
Gene Transfection ◽  
Lysosomal Storage Diseases ◽  
Lessons Learned ◽  
Brain Targeting ◽  
Lysosomal Storage ◽  
Cell Therapies ◽  
Storage Diseases

: Although cross-correction was discovered more than 50 years ago, and held the promise of drastically improving disease management, still no cure exists for lysosomal storage diseases (LSDs). Cell therapies hold the potential to halt disease progression: either a subset of autologous cells can be ex vivo/ in vivo transfected with the functional gene or allogenic wild type stem cells can be transplanted. However, majority of cell-based attempts have been ineffective, due to the difficulties in reversing neuronal symptomatology, in finding appropriate gene transfection approaches, in inducing immune tolerance, reducing the risk of graft versus host disease (GVHD) when allogenic cells are used and that of immune response when engineered viruses are administered, coupled with a limited secretion and uptake of some enzymes. In the last decade, due to advances in our understanding of lysosomal biology and mechanisms of cross-correction, coupled with progresses in gene therapy, ongoing pre-clinical and clinical investigations have remarkably increased. Even gene editing approaches are currently under clinical experimentation. This review proposes to critically discuss and compare trends and advances in cell-based and gene therapy for LSDs. Systemic gene delivery and transplantation of allogenic stem cells will be initially discussed, whereas proposed brain targeting methods will be then critically outlined.

Home-based service for enzyme replacement therapy in lysosomal storage disorders: patient reported outcomes

2018 ◽  
Vol 6 (4) ◽  
pp. 669
Author(s):  
Paolo Tirelli ◽  
Fiorina Giona ◽  
Maja Di Rocco ◽  
Elena Cassinerio ◽  
Antonio Pisani ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Enzyme Replacement Therapy ◽  
Replacement Therapy ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Nursing Service ◽  
Enzyme Replacement ◽  
Home Based ◽  
Patient Reported

Background:  Lysosomal storage diseases (LSDs) are a heterogeneous group of rare chronic genetic conditions. The standard-of-care treatment for LSDs is hospital-based infusion of enzyme replacement therapy (ERT), however, over time this can be stressful and inconvenient. The Italian TuTor program, established in 2011 by Sanofi Genzyme, is a professional nursing service providing home-based ERT to patients with LSDs.Objectives:  The current questionnaire-based study was conducted to investigate the level of patient satisfaction with theTuTor program and to shed light on disease perception.Methods:  Patients were enrolled in the TuTor program from 2011 onwards. The first 100 patients enrolled were interviewed at baseline with follow-up interviews conducted at 6, 12 and 18 months.Results: Overall, 52 patients were female; 46 had Gaucher’s disease, 46 had Fabry disease and 8 had mucopolysaccharidosis type 1. Patients took on average >2 hours to receive hospital-based ERT, plus time associated with the infusion; 2 out of 3 patients needed a caregiver to travel to the hospital. After receiving home-based ERT for 6 months, 37% of patients considered their quality of life ‘greatly improved’ (60% at 18 months). Overall, 99% to 100% of patients rated the home-based nursing service as ‘positive’ or ‘very positive’ and reported that they would recommend the service to other patients with their condition.Conclusions: For patients with LSDs eligible for ERT, a disease-specific home-based nursing service increased their perception of quality of life over a hospital-based service and was advantageous in terms of their time and expenditure.

scholarly journals Inhibition of neutral sphingomyelinase-2 facilitates remyelination

2019 ◽  
Author(s):  
Seung-Wan Yoo ◽  
Amit Agarwal ◽  
Matthew D. Smith ◽  
Saja S. Khuder ◽  
Emily G. Baxi ◽  
...  
Keyword(s):  
Oligodendrocyte Progenitor Cells ◽  
Pharmacological Inhibition ◽  
Myelin Sheaths ◽  
Sphingosine 1 Phosphate ◽  
Secondary Demyelination ◽  
Myelin Thickness ◽  
Genetic Deletion ◽  
Active Caspase

AbstractFor reasons that are not completely understood, remyelination is often incomplete, producing thin myelin sheaths with disorganized structure. We investigated the cellular basis for this altered myelin structure, and found that the response of oligodendrocyte progenitor cells (OPCs), and mature oligodendrocytes to TNFα and IL-1β is modified by the expression of the sphingomyelin hydrolase nSMase2. OPCs do not express nSMase2, and exhibit a protective response to these cytokines manifest by decreased ceramide, increased sphingosine 1-phosphate, and increased cell motility. Mature oligodendrocytes express nSMase2, and respond to TNFα and IL-1β with a stress phenotype, evidenced by increased ceramide, decreased sphingosine, and active caspase 3. Pharmacological inhibition or a targeted genetic deletion of nSMase2in vivoincreased myelin thickness, and enhanced myelin compaction. These results suggest that inhibition of nSMase2 improves the quality of new myelin by protecting maturing/myelinating oligodendrocytes. Pharmacological inhibition of nSMase2 following a demyelinating event could stabilize the structure of these newly formed myelin sheaths and protect them from secondary demyelination.

scholarly journals Lysosomal Leukodystrophies Lysosomal Storage Diseases Associated With White Matter Abnormalities

2019 ◽  
Vol 34 (6) ◽  
pp. 339-358 ◽  
Author(s):  
Gustavo H.B. Maegawa
Keyword(s):  
White Matter ◽  
Metabolic Diseases ◽  
Age Groups ◽  
Clinical Manifestations ◽  
Lysosomal Storage Diseases ◽  
Abnormal Development ◽  
Neurologic Manifestations ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Extrapyramidal Signs

The leukodystrophies are a group of genetic metabolic diseases characterized by an abnormal development or progressive degeneration of the myelin sheath. The myelin is a complex sheath composed of several macromolecules covering axons as an insulator. Each of the leukodystrophies is caused by mutations in genes encoding enzymes that are involved in myelin production and maintenance. The lysosomal storage diseases are inborn disorders of compartmentalized cellular organelles with broad clinical manifestations secondary to the progressive accumulation of undegraded macromolecules within lysosomes and related organelles. The more than 60 different lysosomal storage diseases are rare diseases; however, collectively, the incidence of lysosomal storage diseases ranges just over 1 in 2500 live births. The majority of lysosomal storage diseases are associated with neurologic manifestations including developmental delay, seizures, acroparesthesia, motor weakness, and extrapyramidal signs. These inborn organelle disorders show wide clinical variability affecting individuals from all age groups. In addition, several of neurologic, also known as neuronopathic, lysosomal storage diseases are associated with some level of white matter disease, which often triggers the diagnostic investigation. Most lysosomal storage diseases are autosomal recessively inherited and few are X-linked, with females being at risk of presenting with mild, but clinically relevant neurologic manifestations. Biochemical assays are the basis of the diagnosis and are usually confirmed by molecular genetic testing. Novel therapies have emerged. However, most affected patients with lysosomal storage diseases have only supportive management to rely on. A better understanding of the mechanisms resulting in the leukodystrophy will certainly result in innovative and efficacious disease-modifying therapies.

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