Therapeutic advantages of combined gene/cell therapy strategies in a murine model of GM2 gangliosidosis

The GM2 gangliosidoses Tay-Sachs disease and Sandhoff disease (SD) are respectively caused by mutations in the HEXA and HEXB genes encoding the α and β subunits of β-N-acetylhexosaminidase (Hex). The consequential accumulation of ganglioside in the brain leads to severe and progressive neurological impairment. There are currently no approved therapies to counteract or reverse the effects of GM2 gangliosidosis. Adeno-associated vector (AAV)-based investigational gene therapy (GT) products have raised expectations but come with safety and efficacy issues that need to be addressed. Thus, there is an urgent need to develop novel therapies targeting the CNS and other affected tissues that are appropriately timed to ensure pervasive metabolic correction and counteract disease progression. In this report, we show that the sequential administration of lentiviral vector (LV)-mediated intracerebral (IC) GT and bone marrow transplantation (BMT) in pre-symptomatic SD mice provide a timely and long-lasting source of the Hex enzyme in the central and peripheral nervous systems and peripheral tissues, leading to global rescue of the disease phenotype. Combined therapy showed a clear therapeutic advantage compared to individual treatments in terms of lifespan extension and normalization of the neuroinflammatory and neurodegenerative phenotypes of the SD mice. These benefits correlated with a time-dependent increase in Hex activity and a remarkable reduction in GM2 storage in the brain tissues that single treatments failed to achieve. Our results highlight the complementary and synergic mode of action of LV-mediated IC GT and BMT, clarify the relative contribution of treatments to the therapeutic outcome, and inform on the realistic threshold of enzymatic activity that is required to achieve a significant therapeutic benefit, with important implications for the monitoring and interpretation of ongoing experimental therapies, and for the design of more effective treatment strategies for GM2 gangliosidosis.

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Stem cell therapies for malignant glioma

Neurosurgical FOCUS ◽

10.3171/foc.2005.19.3.6 ◽

2005 ◽

Vol 19 (3) ◽

pp. 1-11 ◽

Cited By ~ 29

Author(s):

Moneeb Ehtesham ◽

Charles B. Stevenson ◽

Reid C. Thompson

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Malignant Glioma ◽

Treatment Strategies ◽

Therapeutic Benefit ◽

Therapeutic Modality ◽

Clinical Implementation ◽

Stem Cell Therapies ◽

Cell Therapies ◽

The Brain

The prognosis for patients with malignant glioma, which is the most common primary intracranial neoplasm, remains dismal despite significant progress in neurooncological therapies and technology. This is largely due to the inability of current treatment strategies to address the highly invasive nature of this disease. Malignant glial cells often disseminate throughout the brain, making it exceedingly difficult to target and treat all intracranial neoplastic foci, with the result that tumor recurrence is inevitable despite aggressive surgery and adjuvant radiotherapy and/or chemotherapy. The use of neural stem cells (NSCs) as delivery vehicles for tumor-toxic molecules represents the first experimental strategy aimed specifically at targeting disseminated tumor pockets. Investigators have demonstrated that NSCs possess robust tropism for infiltrating tumor cells, and that they can be used to deliver therapeutic agents directly to tumor satellites, with significant therapeutic benefit. With the aim of developing these findings into a clinically viable technology that would not be hindered by ethical and tissue rejection–related concerns, the use of adult tissue–derived stem cells has recently been explored. These technologies represent important progress in the development of a treatment strategy that can specifically target disseminated neoplastic pockets within the brain. Despite encouraging results in preclinical models, however, there are significant impediments that must be overcome prior to clinical implementation of this strategy. Key among these are an inadequate understanding of the specific tropic mechanisms that govern NSC migration toward invasive tumor, and the need to refine the processes used to generate tumor-tropic stem cells from adult tissues so that this can be accomplished in a clinically practicable fashion. Despite these limitations, the use of stem cell therapies for brain tumors holds significant promise and may emerge as an important therapeutic modality for patients with malignant glioma.

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Central Nerve System Impairment, AMA Guides, Sixth Edition: An Overview

Guides Newsletter ◽

10.1001/amaguidesnewsletters.2018.janfeb03 ◽

2018 ◽

Vol 23 (1) ◽

pp. 10-13

Author(s):

James B. Talmage ◽

Jay Blaisdell

Keyword(s):

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Neurological Impairment ◽

Sixth Edition ◽

Central Nerve System ◽

The Central Nervous System ◽

The One ◽

Nerve System ◽

The Brain

Abstract Injuries that affect the central nervous system (CNS) can be catastrophic because they involve the brain or spinal cord, and determining the underlying clinical cause of impairment is essential in using the AMA Guides to the Evaluation of Permanent Impairment (AMA Guides), in part because the AMA Guides addresses neurological impairment in several chapters. Unlike the musculoskeletal chapters, Chapter 13, The Central and Peripheral Nervous System, does not use grades, grade modifiers, and a net adjustment formula; rather the chapter uses an approach that is similar to that in prior editions of the AMA Guides. The following steps can be used to perform a CNS rating: 1) evaluate all four major categories of cerebral impairment, and choose the one that is most severe; 2) rate the single most severe cerebral impairment of the four major categories; 3) rate all other impairments that are due to neurogenic problems; and 4) combine the rating of the single most severe category of cerebral impairment with the ratings of all other impairments. Because some neurological dysfunctions are rated elsewhere in the AMA Guides, Sixth Edition, the evaluator may consult Table 13-1 to verify the appropriate chapter to use.

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InsB9-23 Gene Transfer To Hepatocytes-Based Combined Therapy Abrogates Recurrence of Type-1 Diabetes After Islet Transplantation

10.2337/figshare.13135592 ◽

2020 ◽

Author(s):

Ada Admin ◽

Fabio Russo ◽

Antonio Citro ◽

Giorgia Squeri ◽

Francesca Sanvito ◽

...

Keyword(s):

T Regulatory Cells ◽

Lentiviral Vector ◽

Autoimmune Diabetes ◽

Therapeutic Option ◽

Combined Therapy ◽

Cell Mass ◽

Nod Mice ◽

Β Cell ◽

Suboptimal Dose ◽

Islets Transplantation

The induction of antigen (Ag)-specific tolerance represents a therapeutic option for autoimmune diabetes. We demonstrated that administration of lentiviral vector enabling expression of insulinB9-23 (LV.InsB) in hepatocytes, arrests β cell destruction in pre-diabetic NOD mice, by generating InsB9-23-specific FoxP3+T regulatory cells (Tregs). LV.InsB in combination with a suboptimal dose of anti-CD3 mAb (combined therapy, 1X5µg CT5) reverts diabetes and prevents recurrence of autoimmunity following islets transplantation in ~50% of NOD mice. We investigated whether CT optimization could lead to abrogation of recurrence of autoimmunity. Therefore, allo-islets were transplanted after optimized CT tolerogenic conditioning (1X25µg CT25). Diabetic NOD mice conditioned with CT25 when glycaemia was <500mg/dL, remained normoglycaemic for 100 days after allo-islets transplantation, displayed reduced insulitis, but independently from the graft. Accordingly, cured mice showed T cell unresponsiveness to InsB9-23 stimulation and increased Tregs frequency in islets infiltration and pancreatic LN. Additional studies revealed a complex mechanism of Ag-specific immune regulation driven by CT25, in which both Tregs and PDL1 co-stimulation cooperate to control diabetogenic cells, while transplanted islets play a crucial role, although transient, recruiting diabetogenic cells. Therefore, CT25 before allo-islets transplantation represents an Ag-specific immunotherapy to resolve autoimmune diabetes in the presence of residual endogenous β cell mass.

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Role of Flavonoids in Neurodegenerative Disorders with Special Emphasis on Tangeritin

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190916141934 ◽

2019 ◽

Vol 18 (8) ◽

pp. 581-597 ◽

Cited By ~ 1

Author(s):

Ambreen Fatima ◽

Yasir Hasan Siddique

Keyword(s):

Medicinal Plants ◽

Mechanism Of Action ◽

Neurodegenerative Disorders ◽

Treatment Strategies ◽

Dietary Supplementation ◽

Plant Polyphenols ◽

Promising Candidate ◽

Naturally Occurring ◽

The Brain

Flavonoids are naturally occurring plant polyphenols found universally in all fruits, vegetables and medicinal plants. They have emerged as a promising candidate in the formulation of treatment strategies for various neurodegenerative disorders. The use of flavonoid rich plant extracts and food in dietary supplementation have shown favourable outcomes. The present review describes the types, properties and metabolism of flavonoids. Neuroprotective role of various flavonoids and the possible mechanism of action in the brain against the neurodegeneration have been described in detail with special emphasis on the tangeritin.

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Modeling temperature- and Cav3 subtype-dependent alterations in T-type calcium channel mediated burst firing

Molecular Brain ◽

10.1186/s13041-021-00813-7 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Fernando R. Fernandez ◽

Mircea C. Iftinca ◽

Gerald W. Zamponi ◽

Ray W. Turner

Keyword(s):

Calcium Channel ◽

Neuronal Excitability ◽

Neuronal Firing ◽

Mammalian Brain ◽

Peripheral Tissues ◽

Window Current ◽

Modeling Data ◽

The Brain ◽

Firing Neuron ◽

Cav3 Channel

AbstractT-type calcium channels are important regulators of neuronal excitability. The mammalian brain expresses three T-type channel isoforms (Cav3.1, Cav3.2 and Cav3.3) with distinct biophysical properties that are critically regulated by temperature. Here, we test the effects of how temperature affects spike output in a reduced firing neuron model expressing specific Cav3 channel isoforms. The modeling data revealed only a minimal effect on baseline spontaneous firing near rest, but a dramatic increase in rebound burst discharge frequency for Cav3.1 compared to Cav3.2 or Cav3.3 due to differences in window current or activation/recovery time constants. The reduced response by Cav3.2 could optimize its activity where it is expressed in peripheral tissues more subject to temperature variations than Cav3.1 or Cav3.3 channels expressed prominently in the brain. These tests thus reveal that aspects of neuronal firing behavior are critically dependent on both temperature and T-type calcium channel subtype.

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Two patients from Turkey with a novel variant in the GM2A gene and review of the literature

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0655 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Aslı İnci ◽

Filiz Başak Cengiz Ergin ◽

Gürsel Biberoğlu ◽

İlyas Okur ◽

Fatih Süheyl Ezgü ◽

...

Keyword(s):

Sandhoff Disease ◽

Pathogenic Variant ◽

Protein Deficiency ◽

Gm2 Gangliosidosis ◽

Infantile Form ◽

Rare Form ◽

Inborn Errors ◽

Activator Protein ◽

Gm2 Activator ◽

Gm2 Activator Protein

Abstract Objectives GM2 gangliosidosis is a rare form of inborn errors of metabolism including Tay-Sachs disease, Sandhoff disease, and GM2 activator deficiency. GM2 activator protein deficiency is an ultra-rare form of GM2 gangliosidosis. To date, 16 cases of GM2 activator protein deficiency have been reported in the literature, and among them, 11 cases were the infantile form of the disease. Here we report the first two patients from Turkey with the infantile form of the disease with a novel likely pathogenic variant. Case presentation A boy of eight months old presented to the metabolic department with very mild neurological deterioration, although he had achieved early developmental milestones at the appropriate time. The parents also had a daughter who had lost skills progressively before one year of age. The boy was evaluated and bilateral cherry-red spots were found with no abnormality in either metabolic screening including β-hexosaminidase or cranial magnetic resonance imaging. A novel homozygous likely pathogenic variant in GM2A was detected in a next-generation sequence panel revealing GM2 activator protein deficiency. His sister was investigated after he was diagnosed with GM2 activator deficiency and it was found that she had the same variant as her brother. Conclusions This case report emphasizes that in the event of normal β-hexosaminidase activity, GM2 activator protein deficiency could be underdiagnosed, and further molecular analysis should be performed. To the best of our knowledge, this boy is one of the youngest patient diagnosed with very mild symptoms. With this novel pathogenic variant, these patients have expanded the mutation spectrum of GM2 activator protein deficiency.

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Molecular mechanisms of cell death in neurological diseases

Cell Death and Differentiation ◽

10.1038/s41418-021-00814-y ◽

2021 ◽

Author(s):

Diane Moujalled ◽

Andreas Strasser ◽

Jeffrey R. Liddell

Keyword(s):

Cell Death ◽

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

Neuronal Development ◽

Neurological Diseases ◽

Treatment Strategies ◽

Current Treatment ◽

Response To Therapy ◽

Signalling Cascades ◽

The Brain

AbstractTightly orchestrated programmed cell death (PCD) signalling events occur during normal neuronal development in a spatially and temporally restricted manner to establish the neural architecture and shaping the CNS. Abnormalities in PCD signalling cascades, such as apoptosis, necroptosis, pyroptosis, ferroptosis, and cell death associated with autophagy as well as in unprogrammed necrosis can be observed in the pathogenesis of various neurological diseases. These cell deaths can be activated in response to various forms of cellular stress (exerted by intracellular or extracellular stimuli) and inflammatory processes. Aberrant activation of PCD pathways is a common feature in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, resulting in unwanted loss of neuronal cells and function. Conversely, inactivation of PCD is thought to contribute to the development of brain cancers and to impact their response to therapy. For many neurodegenerative diseases and brain cancers current treatment strategies have only modest effect, engendering the need for investigations into the origins of these diseases. With many diseases of the brain displaying aberrations in PCD pathways, it appears that agents that can either inhibit or induce PCD may be critical components of future therapeutic strategies. The development of such therapies will have to be guided by preclinical studies in animal models that faithfully mimic the human disease. In this review, we briefly describe PCD and unprogrammed cell death processes and the roles they play in contributing to neurodegenerative diseases or tumorigenesis in the brain. We also discuss the interplay between distinct cell death signalling cascades and disease pathogenesis and describe pharmacological agents targeting key players in the cell death signalling pathways that have progressed through to clinical trials.

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A feasibility study of mHealth and wearable technology in late onset GM2 gangliosidosis (Tay-Sachs and Sandhoff Disease)

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01473-x ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Elin Haf Davies ◽

Jean Johnston ◽

Camilo Toro ◽

Cynthia J. Tifft

Keyword(s):

Feasibility Study ◽

Late Onset ◽

Sandhoff Disease ◽

Wearable Technology ◽

Gm2 Gangliosidosis

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Understanding Quantitative Circadian Regulations Are Crucial Towards Advancing Chronotherapy

Cells ◽

10.3390/cells8080883 ◽

2019 ◽

Vol 8 (8) ◽

pp. 883 ◽

Cited By ~ 3

Author(s):

Debajyoti Chowdhury ◽

Chao Wang ◽

Ai-Ping Lu ◽

Hai-Long Zhu

Keyword(s):

Circadian Rhythms ◽

Molecular Mechanisms ◽

Temporal Stability ◽

Biological Rhythms ◽

Integrative Approach ◽

Peripheral Tissues ◽

Innovative Strategies ◽

Neural Connections ◽

Core Components ◽

The Brain

Circadian rhythms have a deep impact on most aspects of physiology. In most organisms, especially mammals, the biological rhythms are maintained by the indigenous circadian clockwork around geophysical time (~24-h). These rhythms originate inside cells. Several core components are interconnected through transcriptional/translational feedback loops to generate molecular oscillations. They are tightly controlled over time. Also, they exert temporal controls over many fundamental physiological activities. This helps in coordinating the body’s internal time with the external environments. The mammalian circadian clockwork is composed of a hierarchy of oscillators, which play roles at molecular, cellular, and higher levels. The master oscillation has been found to be developed at the hypothalamic suprachiasmatic nucleus in the brain. It acts as the core pacemaker and drives the transmission of the oscillation signals. These signals are distributed across different peripheral tissues through humoral and neural connections. The synchronization among the master oscillator and tissue-specific oscillators offer overall temporal stability to mammals. Recent technological advancements help us to study the circadian rhythms at dynamic scale and systems level. Here, we outline the current understanding of circadian clockwork in terms of molecular mechanisms and interdisciplinary concepts. We have also focused on the importance of the integrative approach to decode several crucial intricacies. This review indicates the emergence of such a comprehensive approach. It will essentially accelerate the circadian research with more innovative strategies, such as developing evidence-based chronotherapeutics to restore de-synchronized circadian rhythms.

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