gene therapy

摘要： Although little attention has been paid to cognitive and emotional dysfunctions observed in patients after spinal co rd injury,several reports have described impairments in cognitive abilities.Our group also has contributed significantly to the study of cognitive impairments in a rat model of spinal co rd injury.These findings are very significant because they demonstrate that cognitive and mood deficits are not induced by lifestyle changes,drugs of abuse,and combined medication.They are related to changes in brain structures involved in cognition and emotion,such as the hippocampus.Chronic spinal cord injury decreases neurogenesis,enhances glial reactivity leading to hippocampal neuroinflammation,and trigge rs cognitive deficits.These brain distal abnormalities are recently called te rtiary damage.Given that there is no treatment for Tertiary Damage,insulin growth factor 1 gene therapy emerges as a good candidate.Insulin growth factor 1 gene thera py recove rs neurogenesis and induces the polarization from pro-inflammato ry towards anti-inflammatory microglial phenotypes,which represents a potential strategy to treat the neuroinflammation that supports te rtiary damage.Insulin growth factor 1 gene therapy can be extended to other central nervous system pathologies such as traumatic brain injury where the neuroinflammatory component is crucial.Insulin growth factor 1 gene therapy could emerge as a new therapeutic strategy for treating traumatic brain injury and spinal cord injury.

摘要： Charcot-Marie-Tooth neuropathies(CMT)constitute a group of common but highly heterogeneous,non-syndromic genetic disorders affecting predominantly the peripheral nervous system.CMT type 1A(CMT1A)is the most frequent type and accounts for almost~50%of all diagnosed CMT cases.CMT1A results from the duplication of the peripheral myelin protein 22(PMP22)gene.Overexpression of PMP22 protein overloads the protein folding apparatus in Schwann cells and activates the unfolded protein response.This leads to Schwann cell apoptosis,dys-and de-myelination and secondary axonal degeneration,ultimately causing neurological disabilities.During the last decades,several different gene therapies have been developed to treat CMT1A.Almost all of them remain at the pre-clinical stage using CMT1A animal models overexpressing PMP22.The therapeutic goal is to achieve gene silencing,directly or indirectly,thereby reversing the CMT1A genetic mechanism allowing the recovery of myelination and prevention of axonal loss.As promising treatments are rapidly emerging,treatment-responsive and clinically relevant biomarkers are becoming necessary.These biomarkers and sensitive clinical evaluation tools will facilitate the design and successful completion of future clinical trials for CMT1A.

摘要： Post-traumatic spinal cord remodeling includes both degenerating and regenerating processes,which affect the potency of the functional recovery after spinal cord injury(SCI).Gene therapy for spinal cord injury is proposed as a promising therapeutic strategy to induce positive changes in remodeling of the affected neural tissue.In our previous studies for delivering the therapeutic genes at the site of spinal cord injury,we developed a new approach using an autologous leucoconcentrate transduced ex vivo with chimeric adenoviruses(Ad5/35)carrying recombinant cDNA.In the present study,the efficacy of the intravenous infusion of an autologous genetically-enriched leucoconcentrate simultaneously producing recombinant vascular endothelial growth factor(VEGF),glial cell line-derived neurotrophic factor(GDNF),and neural cell adhesion molecule(NCAM)was evaluated with regard to the molecular and cellular changes in remodeling of the spinal cord tissue at the site of damage in a model of mini-pigs with moderate spinal cord injury.Experimental animals were randomly divided into two groups of 4 pigs each:the therapeutic(infused with the leucoconcentrate simultaneously transduced with a combination of the three chimeric adenoviral vectors Ad5/35‐VEGF165,Ad5/35‐GDNF,and Ad5/35‐NCAM1)and control groups(infused with intact leucoconcentrate).The morphometric and immunofluorescence analysis of the spinal cord regeneration in the rostral and caudal segments according to the epicenter of the injury in the treated animals compared to the control mini-pigs showed:(1)higher sparing of the grey matter and increased survivability of the spinal cord cells(lower number of Caspase-3-positive cells and decreased expression of Hsp27);(2)recovery of synaptophysin expression;(3)prevention of astrogliosis(lower area of glial fibrillary acidic protein-positive astrocytes and ionized calcium binding adaptor molecule 1-positive microglial cells);(4)higher growth rates of regeneratingβIII-tubulin-positive axons accompanied by a higher number of oligodendrocyte transcription factor 2-positive oligodendroglial cells in the lateral corticospinal tract region.These results revealed the efficacy of intravenous infusion of the autologous genetically-enriched leucoconcentrate producing recombinant VEGF,GDNF,and NCAM in the acute phase of spinal cord injury on the positive changes in the post-traumatic remodeling nervous tissue at the site of direct injury.Our data provide a solid platform for a new ex vivo gene therapy for spinal cord injury and will facilitate further translation of regenerative therapies in clinical neurology.

摘要： Recent evidence points towards the role of genotype to understand the phenotype,predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis(PFIC).Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified.Treatment of pruritus,nutritional rehabilitation,prevention of fibrosis progression and liver transplantation(LT)in those with end stage liver disease form the crux of the treatment.LT in PFIC has its own unique issues like high rates of intractable diarrhoea,growth failure;steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2.Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.

摘要： Despite the significant progress in cancer therapy,colorectal cancer(CRC)remains one of the most fatal malignancies worldwide.Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment.However,the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability,non-selective tumor targeting mechanisms,non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects.Over the last decade,there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations.Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates.Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect.They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site.They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer.Given that combination therapy is the new strategy implemented in cancer therapy,polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes.They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy.Here,we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment.We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.

摘要： Objective:Although great progress has been made in the field of siRNA gene therapy,safe,efficient,and targeted delivery of siRNA are still major challenges in siRNA therapeutics.Methods:We developed an up-conversion nanoparticle-based nanocage system.This system protected the siRNA from being degraded by nucleases in organisms and selectively delivered the siRNAs to the tumor sites,due to modifications of targeted molecules on the surfaces of nanocages and local inhalation.Results:The siRNAs delivered by the up-conversion nanoparticle nanocages were protected from degradation in transit to the tumor sites,where they accumulated.Compared with the passive target and control groups,the up-conversion nanoparticles based on the nanocage system showed a tumor suppressive effect after approximately 3 weeks of treatment.Conclusions:The up-conversion nanoparticle nanocages efficiently delivered vascular endothelial growth factor siRNAs to tumor sites.Mice with lung tumors treated with tumors targeting up-conversion nanoparticle nanocages showed steady body weight changes,high tumor inhibition ratios,and longer survival times.

摘要： The massive COVID-19 vaccination campaign is the first time that mRNA vaccines have been used on a global scale.The mRNA vaccines correspond exactly to the definition of gene therapy of the American and European regulatory agencies.The regulations require excretion studies of these drugs and their products(the translated proteins).These studies have not been done for mRNA vaccines(nor for adenovirus vaccines).There are numerous reports of symptoms and pathologies identical to the adverse effects of mRNA vaccines in unvaccinated persons in contact with freshly vaccinated persons.It is therefore important to review the state of knowledge on the possible excretion of vaccine nanoparticles as well as mRNA and its product,the spike protein.Vaccine mRNA-carrying lipid nanoparticles spread after injection throughout the body according to available animal studies and vaccine mRNA(naked or in nanoparticles or in natural exosomes)is found in the bloodstream as well as vaccine spike in free form or encapsulated in exosomes(shown in human studies).Lipid nanoparticles(or their natural equivalent,exosomes or extracellular vesicles(EVs))have been shown to be able to be excreted through body fluids(sweat,sputum,breast milk)and to pass the transplacental barrier.These EVs are also able to penetrate by inhalation and through the skin(healthy or injured)as well as orally through breast milk(and why not during sexual intercourse through semen,as this has not been studied).It is urgent to enforce the legislation on gene therapy that applies to mRNA vaccines and to carry out studies on this subject while the generalization of mRNA vaccines is being considered.

摘要： Advanced therapy medicinal products are human medical therapies based on genes,cells,or tissues,and due to their characteristics,they offer new innovative opportunities for the treatment of diseases and injuries,especially for diseases beyond the reach of traditional approaches.These therapies are at the forefront of innovation and have historically been very controversial,although in the last decade they have gained prominence while the number of new advanced therapies has increased every year.In this regard,despite the controversy they may generate,they are expected to dominate the market in the coming decades.Technologies based on advanced therapies are the present and future of medicine and bring us closer to the long-awaited precision medicine.Here we review the field as it stands today,with a focus on the molecular mechanisms that guided the different advanced therapies approved by the European Medicines Agency,their current status,and their legal approval.

摘要： Covalent organic framework(COF)materials have great development value in the biomedical field.However,the huge size and poor dispersion of COF materials severely limit their application.Here we successfully prepared COF nanoparticles with uniform size and good dispersion under the assistance of microwave.By adding some cationic polymers or small amine molecules,the dispersibility of COF could be further improved and its surface charge also increased.The prepared cationic COF nanoparticles(CLZU NPs)had excellent gene transfection ability and good biocompatibility.Designing low-toxic and highefficiency gene carrier is an important mission in the field of gene therapy.This COF-based gene vector provides a new direction for gene carrier design.

摘要： Lentiviral vectors(LVs), derived from human immunodeficiency virus, are powerful tools for modifying the genes of eukaryotic cells such as hematopoietic stem cells and neural cells. With the extensive and in-depth studies on this gene therapy vehicle over the past two decades, LVs have been widely used in both research and clinical trials. For instance, third-generation and selfinactive LVs have been used to introduce a gene with therapeutic potential into the host genome and achieve targeted delivery into specific tissue. When LVs are employed in leukemia, the transduced T cells recognize and kill the tumor B cells;in β-thalassemia, the transduced CD34^(+) cells express normal β-globin;in adenosine deaminase-deficient severe combined immunodeficiency, the autologous CD34^(+) cells express adenosine deaminase and realize immune reconstitution. Overall, LVs can perform significant roles in the treatment of primary immunodeficiency diseases, hemoglobinopathies, B cell leukemia, and neurodegenerative diseases. In this review, we discuss the recent developments and therapeutic applications of LVs. The safe and efficient LVs show great promise as a tool for human gene therapy.