Current Gene Therapy - Volume 17, Issue 5, 2017

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease and prion disease are not timely and effectively treated using conventional therapies. This emphasizes the need for alternative therapeutic approaches. In this respect, gene-based therapies have been adopted as potentially feasible alternative therapies, where the microRNA (miRNA) approach has experienced a great explosion in recent years. Because miRNAs have been shown to be implicated in the pathogenesis of several diseases including neurodegenerative diseases, they are intensely studied as candidates for diagnostic and prognostic biomarkers, as predictors of drug response and as therapeutic agents. In this review, we evaluate the feasibility of both direct and indirect miRNA mimics and inhibitors toward the regulation of neurodegenerative-related genes both in vivo and in vitro models, highlight the advantages and drawbacks associated with miRNA-based therapy, and summarize the relevant techniques and approaches attempted to deliver miRNAs to the central nervous system for therapeutic purposes, with particular regard to the exosomes. Additionally, we describe a new approach that holds great promise for the treatment of a wide range of diseases including neurodegenerative disorders. This approach is based on addressing the incorporation of miRNAs into exosomes to increase the quantity and quality of miRNA packed and delivered to the central nervous system and other sites of action.

Hemoglobinopathies, including severe β-thalassemia and sickle cell disease, represent the most common monogenic disorders worldwide. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only approved curative option for these syndromes, albeit limited to patients having a suitable donor. Gene therapy, by making use of the patient's own hematopoietic stem cells to introduce a normal copy of the β-globin gene by viral vectors, bridged the gap between the need for cure of patients with hemoglobinopathies and the lack of a donor, without incurring the immunological risks of allo-HSCT. However, gene therapy for hemoglobinopathies proved a difficult and elusive goal for decades and only recently, lenti-viral vector gene therapy was successfully transferred to the clinic. Importantly, during the last years, additional curative options for patients with thalassemia and sickle cell disease are being developed, based on the ability to manipulate the genome by employing programmable nucleases and next-generation genome-modifying tools, thus providing the exciting prospects of targeted in-situ gene correction. In this review, we will summarize current developments in the new era of treatment for hemoglobinopathies, elaborate on lessons gained from gene therapy trials and discuss the exciting prospects and challenges of genome editing.

Background: Neurodegenerative diseases comprise a group of disorders for which no treatment is available till date. Stem cell based therapy offers great hope and promise. However, stem cell transplantation is associated with certain disadvantages like poor targeted migration, engraftment and survival of the transplanted cells. Material & Method: Exosomes, a type of extracellular membrane vesicle released by all cell types including stem cells, offer an alternative to stem cell transplantation. Exosome carry a wide array of biomolecules and are implicated in exhibiting substantial benefits in the repair/regeneration of the injured tissue. Thus, exosomes offer an alternative therapeutic approach as a substitute of cell transplantation. In order to utilize exosomes for therapeutic purpose, it is essential to evaluate the appropriate passage number and the dosage to avoid possible cytotoxic effects. Here, we isolated exosomes from different passages of rat bone marrow mesenchymal stem cells (BM-MSC) and analysed the neuroprotective potential of BM-MSC exosomes in an in vitro model of excitotoxicity. Result: Our results demonstrated that the exosomes isolated from early passage of rat BM-MSC exhibited more efficient neuroprotective potential as opposed to later passages derived exosomes. Furthermore, the neuroprotective efficacy of exosome is dosage dependent. i.e. the lower dosage of exosomes was found to be neuroprotective, whereas higher dosage of exosomes (from later passages) was found to be detrimental to neurons. The early passage derived exosomes protected neurons through anti-apoptotic, anti-necrotic and anti-oxidant mechanisms. Conclusion: Our study suggests that adult stem cells derived exosomes could be a potential therapeutic agent to confer neuroprotection in neurodegenerative diseases like Alzheimer's disease.

Background: During last years, DNA vaccine immunogenicity has been optimized by the employment of co-stimulatory molecules and molecular adjuvants. It has been reported that plasmid (pATRex), encompassing the DNA sequence for the von Willebrand A (vWA/A) domain of the Anthrax Toxin Receptor-1 (ANTXR-1, alias TEM8, Tumor Endothelial Marker 8), acts as strong immune adjuvant by inducing formation of insoluble intracellular aggregates. Markedly, we faced with upsetting findings regarding the safety of pATRex as adjuvant since the aggregosome formation prompted to osteopenia in mice. Objective: The present study provides additional evidences about the proteinaceous adjuvants action within bone marrow and questioned regarding the self-aggregation protein adjuvants immunotoxicity on marrow niches. Methods & Results: Using histological, biochemical and proteomic assays we shed light on pATRex effects within bone marrow niche and specifically we evidenced an aplastic-like bone marrow with disrupted cytokine/chemokine production. Conclusion: The above findings provide compelling support to the thesis that adjuvants based on plasmids encoding protein aggregation domains disrupt the physiological features of the bone marrow elements.