GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects, and Current Therapies

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay–Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood–brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g., intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

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GM2 Gangliosidoses: Clinical Features, Pathophysiological Aspects and Current Therapies

10.20944/preprints202007.0137.v2 ◽

2020 ◽

Author(s):

Andres Felipe Leal ◽

Eliana Benincore-Flórez ◽

Daniela Solano-Galarza ◽

Rafael Guillermo Garzón Jaramillo ◽

Olga Yaneth Echeverri-Peña ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Transport ◽

Current Knowledge ◽

Sandhoff Disease ◽

Substrate Reduction Therapy ◽

Hematopoietic Stem ◽

Enzyme Replacement ◽

Central Nervous System Dysfunction ◽

Gm2 Gangliosidoses

GM2 gangliosidoses are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidoses have been described: Tay-Sachs disease, Sandhoff disease, and the AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidoses patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidoses, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g. intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidoses, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

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GM2 Gangliosidosis: Clinical Features and Current Therapies

10.20944/preprints202007.0137.v1 ◽

2020 ◽

Author(s):

Andres Felipe Leal ◽

Eliana Benincore-Flórez ◽

Daniela Solano-Galarza ◽

Rafael Guillermo Garzón Jaramillo ◽

Olga Yaneth Echeverri-Peña ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Protein Transport ◽

Current Knowledge ◽

Sandhoff Disease ◽

Substrate Reduction Therapy ◽

Gm2 Gangliosidosis ◽

Hematopoietic Stem ◽

Enzyme Replacement ◽

Central Nervous System Dysfunction

GM2 gangliosidosis are a group of pathologies characterized by GM2 ganglioside accumulation into the lysosome due to mutations on the genes encoding for the β-hexosaminidases subunits or the GM2 activator protein. Three GM2 gangliosidosis have been described: Tay-Sachs disease, Sandhoff disease, and AB variant. Central nervous system dysfunction is the main characteristic of GM2 gangliosidosis patients that include neurodevelopment alterations, neuroinflammation, and neuronal apoptosis. Currently, there is not approved therapy for GM2 gangliosidosis, but different therapeutic strategies have been studied including hematopoietic stem cell transplantation, enzyme replacement therapy, substrate reduction therapy, pharmacological chaperones, and gene therapy. The blood-brain barrier represents a challenge for the development of therapeutic agents for these disorders. In this sense, alternative routes of administration (e.g. intrathecal or intracerebroventricular) have been evaluated, as well as the design of fusion peptides that allow the protein transport from the brain capillaries to the central nervous system. In this review, we outline the current knowledge about clinical and physiopathological findings of GM2 gangliosidosis, as well as the ongoing proposals to overcome some limitations of the traditional alternatives by using novel strategies such as molecular Trojan horses or advanced tools of genome editing.

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

Current Pharmaceutical Design ◽

10.2174/1381612825666190708213159 ◽

2019 ◽

Vol 25 (17) ◽

pp. 1933-1950 ◽

Cited By ~ 3

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.

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Neuronal Generation from Somatic Stem Cells: Current Knowledge and Perspectives on the Treatment of Acquired and Degenerative Central Nervous System Disorders

Current Gene Therapy ◽

10.2174/1566523034578375 ◽

2003 ◽

Vol 3 (3) ◽

pp. 247-272 ◽

Cited By ~ 25

Author(s):

S. Corti ◽

F. Locatelli ◽

S. Strazzer ◽

M. Guglieri ◽

G. Comi

Keyword(s):

Stem Cells ◽

Central Nervous System ◽

Nervous System ◽

Current Knowledge ◽

Somatic Stem Cells ◽

Central Nervous System Disorders

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Plant Species of Sub-Family Valerianaceae—A Review on Its Effect on the Central Nervous System

Plants ◽

10.3390/plants10050846 ◽

2021 ◽

Vol 10 (5) ◽

pp. 846

Author(s):

Gitishree Das ◽

Han-Seung Shin ◽

Rosa Tundis ◽

Sandra Gonçalves ◽

Ourlad Alzeus G. Tantengco ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Plant Species ◽

Current Knowledge ◽

Biological Properties ◽

In Vivo Studies ◽

Food Species ◽

The Central Nervous System ◽

Preclinical And Clinical Studies

Valerianaceae, the sub-family of Caprifoliaceae, contains more than 300 species of annual and perennial herbs, worldwide distributed. Several species are used for their biological properties while some are used as food. Species from the genus Valeriana have been used for their antispasmodic, relaxing, and sedative properties, which have been mainly attributed to the presence of valepotriates, borneol derivatives, and isovalerenic acid. Among this genus, the most common and employed species is Valerianaofficinalis. Although valerian has been traditionally used as a mild sedative, research results are still controversial regarding the role of the different active compounds, the herbal preparations, and the dosage used. The present review is designed to summarize and critically describe the current knowledge on the different plant species belonging to Valerianaceae, their phytochemicals, their uses in the treatment of different diseases with particular emphasis on the effects on the central nervous system. The available information on this sub-family was collected from scientific databases up until year 2020. The following electronic databases were used: PubMed, Scopus, Sci Finder, Web of Science, Science Direct, NCBI, and Google Scholar. The search terms used for this review included Valerianaceae, Valeriana, Centranthus, Fedia, Patrinia, Nardostachys, Plectritis, and Valerianella, phytochemical composition, in vivo studies, Central Nervous System, neuroprotective, antidepressant, antinociceptive, anxiolytic, anxiety, preclinical and clinical studies.

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Severe Gastrooesophageal Reflux Disease Associated with Foetal Alcohol Syndrome

Case Reports in Pediatrics ◽

10.1155/2012/509253 ◽

2012 ◽

Vol 2012 ◽

pp. 1-3

Author(s):

N. K. Sujay ◽

Matthew Jones ◽

Emma Whittle ◽

Helen Murphy ◽

Marcus K. H. Auth

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Gastrointestinal Tract ◽

Reflux Disease ◽

Prenatal Alcohol Exposure ◽

Case Reports ◽

Alcohol Exposure ◽

Central Nervous System Dysfunction ◽

Foetal Alcohol Syndrome ◽

Gastrooesophageal Reflux

Prenatal alcohol exposure may have adverse effects on the developing foetus resulting in significant growth restriction, characteristic craniofacial features, and central nervous system dysfunction. The toxic effects of alcohol on the developing brain are well recognised. However, little is known about the effects of alcohol on the developing gastrointestinal tract or their mechanism. There are few case reports showing an association between foetal alcohol syndrome and gastrointestinal neuropathy. We report a rare association between foetal alcohol syndrome and severe gastrooesophageal reflux disease in an infant who ultimately required fundoplication to optimise her growth and nutrition. The child had failed to respond to maximal medical treatment (domperidone and omeprazole), high calorie feeds, PEG feeding, or total parenteral nutrition. The effect of alcohol on the developing foetus is not limited to the central nervous system but also can have varied and devastating effects on the gastrointestinal tract.

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Prognosis and risk factors for central nervous system relapse after allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

Annals of Hematology ◽

10.1007/s00277-020-04380-0 ◽

2021 ◽

Author(s):

Qi Chen ◽

Xiao-Lu Zhu ◽

Xin Zhao ◽

Xiao Liu ◽

Hai-Xia Fu ◽

...

Keyword(s):

Risk Factors ◽

Central Nervous System ◽

Nervous System ◽

Acute Myeloid Leukemia ◽

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Central Nervous System Relapse ◽

Hematopoietic Stem ◽

Acute Myeloid

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CENTRAL NERVOUS SYSTEM INVOLVEMENT IN ADULT ACUTE LYMPHOBLASTIC LEUKEMIA: DIAGNOSTIC TOOLS, PROPHYLAXIS AND THERAPY

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2014.075 ◽

2014 ◽

Vol 6 (1) ◽

pp. e2014075 ◽

Cited By ~ 22

Author(s):

Maria Ilaria Del Principe ◽

Luca Maurillo ◽

Francesco Buccisano ◽

Giuseppe Sconocchia ◽

Mariagiovanna Cefalo ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Intrathecal Injection ◽

False Negative ◽

Diagnostic Tools ◽

Positive Finding ◽

Cns Involvement ◽

Hematopoietic Stem

In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM). Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. Actually, early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogenic hematopoietic stem cell transplantation might be considered. This review will discuss risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it.

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