Perinatal Gene Transfer to the Liver

The liver acts as a host to many functions hence raising the possibility that any one may be compromised by a single gene defect. Inherited or de novo mutations in these genes may result in relatively mild diseases or be so devastating that death within the first weeks or months of life is inevitable. Some diseases can be managed using conventional medicines whereas others are, as yet, untreatable. In this review we consider the application of early intervention gene therapy in neonatal and fetal preclinical studies. We appraise the tools of this technology, including lentivirus, adenovirus and adeno-associated virus (AAV)-based vectors. We highlight the application of these for a range of diseases including hemophilia, urea cycle disorders such as ornithine transcarbamylase deficiency, organic acidemias, lysosomal storage diseases including mucopolysaccharidoses, glycogen storage diseases and bile metabolism. We conclude by assessing the advantages and disadvantages associated with fetal and neonatal liver gene transfer

Using Stem Cells to Grow Artificial Tissue for Peripheral Nerve Repair

Peripheral nerve injury continues to pose a clinical hurdle despite its frequency and advances in treatment. Unlike the central nervous system, neurons of the peripheral nervous system have a greater ability to regenerate. However, due to a number of confounding factors, this is often both incomplete and inadequate. The lack of supportive Schwann cells or their inability to maintain a regenerative phenotype is a major factor. Advances in nervous system tissue engineering technology have led to efforts to build Schwann cell scaffolds to overcome this and enhance the regenerative capacity of neurons following injury. Stem cells that can differentiate along a neural lineage represent an essential resource and starting material for this process. In this review, we discuss the different stem cell types that are showing promise for nervous system tissue engineering in the context of peripheral nerve injury. We also discuss some of the biological, practical, ethical, and commercial considerations in using these different stem cells for future clinical application

Growth response of eight tropical turfgrass species to salinity

Irrigation seawater of different salinity levels (0, 24, 48 and 72 dSm-1) were applied to experimental plants grown in a plastic pots filled with a mixture of sand and peat (9:1). The results were analyzedusing SAS and treatment means were compared using LSD Test. The results indicated that Paspalum vaginatum (seashore paspalum) (SP), Zoysia matrella (manilagrass) (MG), Pasplaum vaginatum local(SPL), Cynodon dactylon (common bermuda) (CB), Cynodon dactylon (bermuda greenless park) (GLP), Eremochloa ophiuroides (centipede) (CP), Axonopus compressus (cow grass) (CG) and Axonopusaffinis (narrowleaf carpet grass) (NCG) experienced a 50% shoot growth reduction at the EC of 39.8, 36.5, 26.1, 25.9, 21.7, 22.4, 17.0 and 18.3 dSm-1, respectively, and a 50% root growth reduction at the ECof 49.4, 42.1, 29.9, 29.7, 26.0 24.8, 18.8 and 20.0 dSm-1, respectively. The ranking for salinity tolerance of selected grasses was  SP>MG>SPL>CB>GLP>CP>NCG>CG. The results indicate the importance of the selection of turfgrass varieties according to the soil salinity and seawater salinity levels to be used for irrigation

Combining gene and stem cell therapy for peripheral nerve tissue engineering

Despite a substantially increased understanding of neuropathophysiology, insufficient functional recovery after peripheral nerve injury (PNI) remains a significant clinical challenge. Nerve regeneration following injury is dependent on Schwann cells, the supporting cells in the peripheral nervous system. Following nerve injury, Schwann cells adopt a pro-regenerative phenotype which supports and guides regenerating nerves. However, this phenotype may not persist long enough to ensure functional recovery. Tissue engineered nerve repair devices containing therapeutic cells that maintain the appropriate phenotype may help enhance nerve regeneration. The combination of gene and cell therapy is an emerging experimental strategy which seeks to provide the optimal environment for axonal regeneration and re-establishment of functional circuits. This review aims to summarise current pre-clinical evidence with potential for future translation from bench to bedside

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development

Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years

A GLP1 receptor agonist diabetes drug ameliorates neurodegeneration in a mouse model of infantile neurometabolic disease

Infantile neuroaxonal dystrophy (INAD) is a rare paediatric neurodegenerative condition caused by mutations in the PLA2G6 gene, which is also the causative gene for PARK14-linked young adult-onset dystonia parkinsonism. INAD patients usually die within their first decade of life, and there are currently no effective treatments available. GLP1 receptor (GLP-1R) agonists are licensed for treating type 2 diabetes mellitus but have also demonstrated neuroprotective properties in a clinical trial for Parkinson's disease. Therefore, we evaluated the therapeutic efficacy of a new recently licensed GLP-1R agonist diabetes drug in a mouse model of INAD. Systemically administered high-dose semaglutide delivered weekly to juvenile INAD mice improved locomotor function and extended the lifespan. An investigation into the mechanisms underlying these therapeutic effects revealed that semaglutide significantly increased levels of key neuroprotective molecules while decreasing those involved in pro-neurodegenerative pathways. The expression of mediators in both the apoptotic and necroptotic pathways were also significantly reduced in semaglutide treated mice. A reduction of neuronal loss and neuroinflammation was observed. Finally, there was no obvious inflammatory response in wild-type mice associated with the repeated high doses of semaglutide used in this study

Mitochondria and Quality Control Defects in a Mouse Model of Gaucher Disease-Links to Parkinson's Disease

Mutations in the glucocerebrosidase (gba) gene cause Gaucher disease (GD), the most common lysosomal storage disorder, and increase susceptibility to Parkinson’s disease (PD). While the clinical and pathological features of idiopathic PD and PD related to gba (PD-GBA) mutations are very similar, cellular mechanisms underlying neurodegeneration in each are unclear. Using a mouse model of neuronopathic GD, we show that autophagic machinery and proteasomal machinery are defective in neurons and astrocytes lacking gba. Markers of neurodegeneration—p62/SQSTM1, ubiquitinated proteins, and insoluble α-synuclein—accumulate. Mitochondria were dysfunctional and fragmented, with impaired respiration, reduced respiratory chain complex activities, and a decreased potential maintained by reversal of the ATP synthase. Thus a primary lysosomal defect causes accumulation of dysfunctional mitochondria as a result of impaired autophagy and dysfunctional proteasomal pathways. These data provide conclusive evidence for mitochondrial dysfunction in GD and provide insight into the pathogenesis of PD and PD-GBA

Impaired cellular bioenergetics caused by GBA1 depletion sensitizes neurons to calcium overload

Heterozygous mutations of the lysosomal enzyme glucocerebrosidase (GBA1) represent the major genetic risk for Parkinson’s disease (PD), while homozygous GBA1 mutations cause Gaucher disease, a lysosomal storage disorder, which may involve severe neurodegeneration. We have previously demonstrated impaired autophagy and proteasomal degradation pathways and mitochondrial dysfunction in neurons from GBA1 knockout (gba1^{-/-}) mice. We now show that stimulation with physiological glutamate concentrations causes pathological [Ca^{2+}]_{c} esponses and delayed calcium deregulation, collapse of mitochondrial membrane potential and an irreversible fall in the ATP/ADP ratio. Mitochondrial Ca^{2+} uptake was reduced in gba1^{−/−} cells as was expression of the mitochondrial calcium uniporter. The rate of free radical generation was increased in gba1^{−/−} neurons. Behavior of gba1^{+/−} neurons was similar to gba1^{−/−} in terms of all variables, consistent with a contribution of these mechanisms to the pathogenesis of PD. These data signpost reduced bioenergetic capacity and [Ca^{2+}]_{c} dysregulation as mechanisms driving neurodegeneration

Corrosion Resistance of AA6063-Type Al-Mg-Si Alloy by Silicon Carbide in Sodium Chloride Solution for Marine Application

The present work focused on corrosion inhibition of AA6063 type Al-Mg-Si alloy in sodium chloride (NaCl) solution with a silicon carbide inhibitor, using the potentiodynamic electrochemical method. The aluminium alloy surface morphology was examined, in the as-received and as-corroded in the un-inhibited state, with scanning electron microscopy equipped with energy dispersive spectroscopy (SEM-EDS). The results obtained via linear polarization indicated a high corrosion potential for the unprotected as-received alloy. Equally, inhibition efficiency as high as 98.82% at 10.0 g/v silicon carbide addition was obtained with increased polarization resistance (Rp), while the current density reduced significantly for inhibited samples compared to the un-inhibited aluminium alloy. The adsorption mechanism of the inhibitor aluminium alloy follows the Langmuir adsorption isotherm. This shows that the corrosion rate of aluminium alloy with silicon carbide in NaCl environment decreased significantly with addition of the inhibito