Current Issue : July-September Volume : 2023 Issue Number : 3 Articles : 5 Articles
Hematopoietic stem and progenitor cells (HSPCs) can establish a long-lasting microglia-like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses due to palmitoylprotein thioesterase-1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild-type HSPCs exerts partial but long-lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over-expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs transplant, with first demonstration of such a dose–effect benefit for a purely neurodegenerative condition like CLN1 disease; (iii) transplantation of hPPT1 over-expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1- symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals. Overall, these findings provide first evidence of efficacy and feasibility of this novel approach to treat CLN1 disease and possibly other neurodegenerative conditions, paving the way for its future clinical application....
Therapies for Leber hereditary optic neuropathy (LHON), in common with all disorders caused by mutated mitochondrial DNA, are inadequate. We have developed two gene therapy strategies for the disease: mitochondrial-targeted and allotopic expressed and compared them in a mouse model of LHON. Methods: A LHON mouse model was generated by intravitreal injection of a mitochondrialtargeted Adeno-associated virus (AAV) carrying mutant human NADH dehydrogenase 4 gene (hND4/m.11778G>A) to induce retinal ganglion cell (RGC) degeneration and axon loss, the hallmark of the human disease. We then attempted to rescue those mice using a second intravitreal injection of either mitochondrialtargeted or allotopic expressed wildtype human ND4. The rescue of RGCs and their axons were assessed using serial pattern electroretinogram (PERG) and transmission electron microscopy. Results: Compared to non-rescued LHON controls where PERG amplitude was much reduced, both strategies significantly preserved PERG amplitude over 15 months. However, the rescue effect was more marked with mitochondrial-targeted therapy than with allotopic therapy (p = 0.0128). Post-mortem analysis showed that mitochondrial-targeted human ND4 better preserved small axons that are preferentially lost in human LHON. Conclusions: These results in a pre-clinical mouse model of LHON suggest that mitochondrially-targeted AAV gene therapy, compared to allotopic AAV gene therapy, is more efficient in rescuing the LHON phenotype....
The homozygous genotype of the Longevity-Associated Variant (LAV) in Bactericidal/ Permeability-Increasing Fold-Containing Family B member 4 (BPIFB4) is enriched in long-living individuals of three independent populations and its genetic transfer in C57BL/6J mice showed a delay in frailty progression and improvement of several biomarkers of aging and multiple aspects of health. The C57BL/6J strain is a suitable model for studying therapies aimed at extending healthy aging and longevity due to its relatively short lifespan and the availability of aging biomarkers. Epigenetic clocks based on DNA methylation profiles are reliable molecular biomarkers of aging, while frailty measurement tools are used to evaluate overall health during aging. In this study, we show that the systemic gene transfer of LAV-BPIFB4 in aged C57BL/6J mice was associated with a significant reduction in the epigenetic clock-based biological age, as measured by a three CpG clock method. Furthermore, LAV-BPIFB4 gene transfer resulted in an improvement of the Vitality Score with a reduction in the Frailty Index. These findings further support the use of LAV-BPIFB4 gene therapy to induce beneficial effects on epigenetic mechanisms associated with aging and frailty in aged mice, with potential implications for future therapies to prevent frailty in humans....
The development of effective disease-modifying therapies to halt Parkinson’s disease (PD) progression is required. In a subtype of PD patients, alpha-synuclein pathology may start in the enteric nervous system (ENS) or autonomic peripheral nervous system. Consequently, strategies to decrease the expression of alpha-synuclein in the ENS will be an approach to prevent PD progression at pre-clinical stages in these patients. In the present study, we aimed to assess if anti-alpha-synuclein shRNA-minicircles (MC) delivered by RVG-extracellular vesicles (RVG-EV) could downregulate alpha-synuclein expression in the intestine and spinal cord. RVG-EV containing shRNA-MC were injected intravenously in a PD mouse model, and alpha-synuclein downregulation was evaluated by qPCR and Western blot in the cord and distal intestine. Our results confirmed the downregulation of alpha-synuclein in the intestine and spinal cord of mice treated with the therapy. We demonstrated that the treatment with anti-alpha-synuclein shRNA-MC RVG-EV after the development of pathology is effective to downregulate alpha-synuclein expression in the brain as well as in the intestine and spinal cord. Moreover, we confirmed that a multidose treatment is necessary to maintain downregulation for long-term treatments. Our results support the potential use of anti-alphasynuclein shRNA-MC RVG-EV as a therapy to delay or halt PD pathology progression....
The search for an effective treatment of allergic conditions is an ongoing global health challenge due to the high prevalence of allergies. Epinephrine and glucocorticosteroids remain the oldest and most widely used treatment regimen for allergy, and these medications are for short relief. In extreme allergy manifestations, the current treatment options aim to use monoclonal antibody (mAb) to target pathological pathways of inflammation involving mast cells, eosinophils, and basophils. These cells have the propensity to induce an allergic-inflammatory response. Studies have shown that they are responsible for several allergic diseases, such as allergic asthma, atopic dermatitis, rhinitis, and conjunctivitis. Studies evaluating monoclonal antibodies against serum IgE (Omalizumab), Th-2 cytokines, such as IL-4, IL-13 (dupilumab), and IL-5 suggest an attenuation of allergic symptoms and improvement in patients’ overall well-being. However, several factors such as cost of production (i.e., antibody purification), host immunogenicity, safety, and efficacy have hindered the availability of purified mAb in developing countries. Gene therapy is a promising tool for treating allergy, and emerging studies have suggested that antibody gene therapy may be the future for treating extreme cases of allergy manifestations. This paper describes the use of purified monoclonal antibodies for treating severe allergic responses and the associated limitations. It explores the prospects of antibody gene therapy for modulating allergy episodes....
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