LYSOSOME STORAGE DISORDERS ON THE BRAIN: THE AUTOPHAGY LYSOSOME PATHWAY CONTRIBUTES TO DISEASE PATHOPHYSIOLOGY AND MAY BE UTILIZED FOR THERAPEUTIC BENEFIT

2012 ◽  
pp. 331-354
Author(s):  
John J. Shacka
Keyword(s):  
Therapeutic Benefit ◽  
The Brain ◽  
Storage Disorders

scholarly journals Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831769979 ◽  
Author(s):  
Richard E Kast ◽  
Quentin A Hill ◽  
Didier Wion ◽  
Håkan Mellstedt ◽  
Daniele Focosi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Antiviral Drug ◽  
Therapeutic Benefit ◽  
Lipid Lowering ◽  
Common Finding ◽  
European Medicines Agency ◽  
Gm Csf ◽  
Growth Promoting ◽  
The Brain ◽  
Potential Therapeutic Benefit

Increased ratio of circulating neutrophils to lymphocytes is a common finding in glioblastoma and other cancers. Data reviewed establish that any damage to brain tissue tends to cause an increase in G-CSF and/or GM-CSF (G(M)-CSF) synthesized by the brain. Glioblastoma cells themselves also synthesize G(M)-CSF. G(M)-CSF synthesized by brain due to damage by a growing tumor and by the tumor itself stimulates bone marrow to shift hematopoiesis toward granulocytic lineages away from lymphocytic lineages. This shift is immunosuppressive and generates the relative lymphopenia characteristic of glioblastoma. Any trauma to brain—be it blunt, sharp, ischemic, infectious, cytotoxic, tumor encroachment, or radiation—increases brain synthesis of G(M)-CSF. G(M)-CSF are growth and motility enhancing factors for glioblastomas. High levels of G(M)-CSF contribute to the characteristic neutrophilia and lymphopenia of glioblastoma. Hematopoietic bone marrow becomes entrained with, directed by, and contributes to glioblastoma pathology. The antibiotic dapsone, the lipid-lowering agent fenofibrate, and the antiviral drug ribavirin are Food and Drug Administration– and European Medicines Agency–approved medicines that have potential to lower synthesis or effects of G(M)-CSF and thus deprive a glioblastoma of some of the growth promoting contributions of bone marrow and G(M)-CSF.

scholarly journals Prion protein lowering is a disease-modifying therapy across prion disease stages, strains and endpoints

2020 ◽  
Vol 48 (19) ◽  
pp. 10615-10631 ◽  
Author(s):  
Eric Vallabh Minikel ◽  
Hien T Zhao ◽  
Jason Le ◽  
Jill O’Moore ◽  
Rose Pitstick ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Onset ◽  
Therapeutic Benefit ◽  
Dosing Regimen ◽  
Prion Strain ◽  
Disease Modifying Therapy ◽  
Prion Strains ◽  
Disease Stages ◽  
The Brain

Abstract Lowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that <25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

Long-term brain network reorganization predicts responsive neurostimulation outcomes for focal epilepsy

2021 ◽  
Vol 13 (608) ◽  
pp. eabf6588
Author(s):  
Ankit N. Khambhati ◽  
Alia Shafi ◽  
Vikram R. Rao ◽  
Edward F. Chang
Keyword(s):  
Therapeutic Response ◽  
Focal Epilepsy ◽  
Therapeutic Benefit ◽  
Brain Network ◽  
First Year ◽  
Seizure Reduction ◽  
Neural Recordings ◽  
Brain Network Reorganization ◽  
The Brain

Responsive neurostimulation (RNS) devices, able to detect imminent seizures and to rapidly deliver electrical stimulation to the brain, are effective in reducing seizures in some patients with focal epilepsy. However, therapeutic response to RNS is often slow, is highly variable, and defies prognostication based on clinical factors. A prevailing view holds that RNS efficacy is primarily mediated by acute seizure termination; yet, stimulations greatly outnumber seizures and occur mostly in the interictal state, suggesting chronic modulation of brain networks that generate seizures. Here, using years-long intracranial neural recordings collected during RNS therapy, we found that patients with the greatest therapeutic benefit undergo progressive, frequency-dependent reorganization of interictal functional connectivity. The extent of this reorganization scales directly with seizure reduction and emerges within the first year of RNS treatment, enabling potential early prediction of therapeutic response. Our findings reveal a mechanism for RNS that involves network plasticity and may inform development of next-generation devices for epilepsy.

scholarly journals Cribriform pattern in brain MRI: A diagnostic clue for mucopolysaccharidoses

2013 ◽  
Vol 17 (4) ◽  
pp. 147-148
Author(s):  
Shamick Biswas ◽  
Sumit Chakraborty
Keyword(s):  
Brain Mri ◽  
Chain Complex ◽  
Perivascular Spaces ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolase ◽  
Diagnostic Clue ◽  
The Brain ◽  
Brain Study ◽  
Long Chain ◽  
Storage Disorders

Mucopolysaccharidoses (MPS) represents a heterogeneous group of inherited lysosomal storage disorders characterised by defective degradation of long-chain complex carbohydrates called glycosoaminoglycans (GAGs). To date, 11 distinct types of MPS have been described, each as a result of deficient enzymatic activity of specific lysosomal hydrolase. The most common types are Hurler and Hunter syndromes. We report a case of a child presenting with macrocephaly, clinically suspected to be due to hydrocephalus. An MRI (3 Tesla) brain study demonstrated the cribriform pattern in the brain caused by dilated perivascular spaces, which is a diagnostic clue for the presence of MPS.

scholarly journals Prion protein lowering is a disease-modifying therapy across prion disease stages, strains, and endpoints

2020 ◽  
Author(s):  
Eric Vallabh Minikel ◽  
Hien T Zhao ◽  
Jason Le ◽  
Jill O’Moore ◽  
Rose Pitstick ◽  
...  
Keyword(s):  
Prion Protein ◽  
Prion Disease ◽  
Disease Onset ◽  
Therapeutic Benefit ◽  
Dosing Regimen ◽  
Prion Strain ◽  
Disease Modifying Therapy ◽  
Prion Strains ◽  
Disease Stages ◽  
The Brain

AbstractLowering of prion protein (PrP) expression in the brain is a genetically validated therapeutic hypothesis in prion disease. We recently showed that antisense oligonucleotide (ASO)-mediated PrP suppression extends survival and delays disease onset in intracerebrally prion-infected mice in both prophylactic and delayed dosing paradigms. Here, we examine the efficacy of this therapeutic approach across diverse paradigms, varying the dose and dosing regimen, prion strain, treatment timepoint, and examining symptomatic, survival, and biomarker readouts. We recapitulate our previous findings with additional PrP-targeting ASOs, and demonstrate therapeutic benefit against four additional prion strains. We demonstrate that less than 25% PrP suppression is sufficient to extend survival and delay symptoms in a prophylactic paradigm. Rise in both neuroinflammation and neuronal injury markers can be reversed by a single dose of PrP-lowering ASO administered after the detection of pathological change. Chronic ASO-mediated suppression of PrP beginning at any time up to early signs of neuropathology confers benefit similar to constitutive heterozygous PrP knockout. Remarkably, even after emergence of frank symptoms including weight loss, a single treatment prolongs survival by months in a subset of animals. These results support ASO-mediated PrP lowering, and PrP-lowering therapeutics in general, as a promising path forward against prion disease.

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

2021 ◽  
Author(s):  
Davide Sala ◽  
Francesca Ornaghi ◽  
Francesco Morena ◽  
Chiara Argentati ◽  
Manuela Valsecchi ◽  
...  
Keyword(s):  
Lentiviral Vector ◽  
Combined Therapy ◽  
Treatment Strategies ◽  
Sandhoff Disease ◽  
Neurological Impairment ◽  
Therapeutic Benefit ◽  
Gm2 Gangliosidosis ◽  
Peripheral Tissues ◽  
Sequential Administration ◽  
The Brain

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.

scholarly journals Therapeutic Potential of Canine Glial Restricted Progenitors Transplanted in Mouse Model of Demyelinating Disease 

2020 ◽  
Author(s):  
Luiza Stanaszek ◽  
Malgorzata Majchrzak ◽  
Katarzyna Drela ◽  
Piotr Rogujski ◽  
Joanna Sanford ◽  
...  
Keyword(s):  
Demyelinating Disease ◽  
Therapeutic Potential ◽  
Companion Animals ◽  
Therapeutic Benefit ◽  
Posterior Aspect ◽  
Cell Behaviour ◽  
Animal Survival ◽  
The Central Nervous System ◽  
The Brain ◽  
Selection Of

Abstract Background: Dysfunction of glia contributes to the deterioration of the central nervous system in a wide array of neurological disorders, thus global replacement strategies of glia are very attractive. Human glial restricted precursors (hGRPs) transplanted intraventricularly into neonatal mice extensively migrated and rescued lifespan in half of studied mice, while mouse GRPs (mGRPs) presented no therapeutic benefit. We hypothesized that the intrinsic developmental program (IDP) might be one of the main drivers of cell behaviour after grafting, with long migration distance and late myelination for hGRPs, compared to limited migration and early myelination for mGRPs. We studied in the same experimental setting canine GRPs (cGRP) to determine whether their migration, myelination and subsequent therapeutic potential falls between hGRPs and mGRPs. Additional motivation for selection of cGRPs was a potential for use in veterinary medicine due to growing population of dogs as companion animals. Methods: cGRPs were extracted from the brain of dog foetuses. The cells transplanted (4x105 cells) into anterior or posterior aspect of the lateral ventricle (LV) of neonatal, immunodeficient, dysmyelinated mice (shiverer, MBPshi/shi, rag2-/-). Outcome measures included early cell biodistribution, animal survival and myelination assessed with MRI, immunohistochemistry and electron microscopy. Results: Grafting of cGRP into posterior LV significantly extended animal survival, while no benefit was observed after anterior LV transplantation. In contrast, myelination of the corpus callosum was more prominent in anteriorly transplanted animals. Conclusions: The extended survival of animals after transplantation of cGRPs could be explained by the vicinity of transplant near the brain stem.

scholarly journals Interleukin-1 Receptor Antagonist Penetrates Human Brain at Experimentally Therapeutic Concentrations

2007 ◽  
Vol 28 (2) ◽  
pp. 387-394 ◽  
Author(s):  
Simon R Clark ◽  
Catherine J McMahon ◽  
Iva Gueorguieva ◽  
Malcolm Rowland ◽  
Sylvia Scarth ◽  
...  
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Cerebral Ischaemia ◽  
Interleukin 1 ◽  
Therapeutic Benefit ◽  
Focal Cerebral Ischaemia ◽  
Interleukin 1 Receptor Antagonist ◽  
Ischaemic Brain ◽  
Steady State Plasma Concentration ◽  
The Brain

The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12±2 μg/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22 ± 4 μg/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.

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