scholarly journals Gene Therapy: A Promising Therapeutic Strategy for Malaria

2018 ◽  
Vol 8 (2) ◽  
pp. 40-44
Author(s):  
Raafay Shehzad
Keyword(s):  
Gene Therapy ◽  
Therapeutic Strategy ◽  
Homing Endonuclease ◽  
Genetic Material ◽  
Gene Drive ◽  
Treatment And Prevention ◽  
Preventative Measures ◽  
Drive Systems ◽  
Embryonic Arrest ◽  
Diabetes And Obesity

Malaria is a serious illness caused by the Plasmodium parasite, which places approximately 3.5 billion people at risk. Currently, preventative measures are key in combatting this disease. However, gene therapy is an emerging field that shows promising results for the treatment of malaria, by modifying cells through the delivery of genetic material. Most notable was the discovery of CRISPR-Cas9, which not only allows deleterious mutations to be repaired, but does so with specificity, speed, and simplicity. There are numerous ongoing trials focusing on gene therapy in malaria treatment and prevention. They involve different approaches such as the genetic modification of vector mosquitoes to interfere with malaria transmission, use of CRISPR-Cas9, maternal-effect dominant embryonic arrest, homing endonuclease gene drive systems, and the design of specific Morpholino oligomers to interfere with the expression of parasitic characteristics. Overall, this emerging field shows promising results to treat and prevent not just malaria, but other diseases such as cancer, diabetes, and obesity.

scholarly journals Modeling the mutation and reversal of engineered underdominance gene drives

2018 ◽  
Author(s):  
Matthew P. Edgington ◽  
Luke S. Alphey
Keyword(s):  
Genetic Material ◽  
Theoretical Work ◽  
The Other ◽  
Lethal Gene ◽  
Gene Drive ◽  
Loss Of Function ◽  
Wild Type ◽  
Type Population ◽  
Drive Systems ◽  
Gene Drives

AbstractA range of gene drive systems have been proposed that are predicted to increase their frequency and that of associated desirable genetic material even if they confer a fitness cost on individuals carrying them. Engineered underdominance (UD) is such a system and, in one version, is based on the introduction of two independently segregating transgenic constructs each carrying a lethal gene, a suppressor for the lethal at the other locus and a desirable genetic “cargo”. Under this system individuals carrying at least one copy of each construct (or no copies of either) are viable whilst those that possess just one of the transgenic constructs are non-viable. Previous theoretical work has explored various properties of these systems, concluding that they should persist indefinitely in absence of resistance or mutation. Here we study a population genetics model of UD gene drive that relaxes past assumptions by allowing for loss-of-function mutations in each introduced gene. We demonstrate that mutations are likely to cause UD systems to break down, eventually resulting in the elimination of introduced transgenes. We then go on to investigate the potential of releasing “free suppressor” carrying individuals as a new method for reversing UD gene drives and compare this to the release of wild-types; the only previously proposed reversal strategy for UD. This reveals that while free suppressor carrying individuals may represent an inexpensive reversal strategy due to extremely small release requirements, they are not able to return a fully wild-type population as rapidly as the release of wild-types.

scholarly journals Lethal Gene Drive Selects Inbreeding

2016 ◽  
Author(s):  
J J Bull
Keyword(s):  
Segregation Distortion ◽  
Essential Gene ◽  
Homing Endonuclease ◽  
Lethal Gene ◽  
Gene Drive ◽  
Partial Restoration ◽  
Selfish Gene ◽  
Evolutionary Response ◽  
Drive Systems ◽  
Population Suppression

AbstractThe use of ‘selfish’ gene drive systems to suppress or even extinguish populations has been proposed on theoretical grounds for almost half a century. Creating these genes has recently become possible with CRISPR technology. One seemingly feasible approach, originally proposed by Burt, is to create a homing endonuclease gene (HEG) that inserts into an essential gene, enabling heterozygote viability but causing homozygote lethality. With 100% segregation distortion in gametes, such genes can cause profound population suppression if resistance does not evolve. Here, population genetic models are used to consider the evolution of inbreeding (specifically selfing) as a possible response to a recessively lethal HEG with complete segregation distortion. Numerical analyses indicate a rich set of outcomes, but selfing often evolves in response to the HEG, with a corresponding partial restoration of mean fitness. Whether selfing does indeed evolve and its effect in restoring fitness depends heavily on the magnitude of inbreeding depression. Overall, these results point toward an underappreciated evolutionary response to block the harmful effects of a selfish gene. They raise the possibility that extreme population suppression may be more difficult to achieve than currently imagined.

scholarly journals How Far Are Non-Viral Vectors to Come of Age and Reach Clinical Translation in Gene Therapy?

2021 ◽  
Vol 22 (14) ◽  
pp. 7545
Author(s):  
Myriam Sainz-Ramos ◽  
Idoia Gallego ◽  
Ilia Villate-Beitia ◽  
Jon Zarate ◽  
Iván Maldonado ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Practice ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Viral Vector ◽  
Clinical Success ◽  
Genetic Material ◽  
Viral Gene ◽  
Promising Alternative ◽  
Vector Systems

Efficient delivery of genetic material into cells is a critical process to translate gene therapy into clinical practice. In this sense, the increased knowledge acquired during past years in the molecular biology and nanotechnology fields has contributed to the development of different kinds of non-viral vector systems as a promising alternative to virus-based gene delivery counterparts. Consequently, the development of non-viral vectors has gained attention, and nowadays, gene delivery mediated by these systems is considered as the cornerstone of modern gene therapy due to relevant advantages such as low toxicity, poor immunogenicity and high packing capacity. However, despite these relevant advantages, non-viral vectors have been poorly translated into clinical success. This review addresses some critical issues that need to be considered for clinical practice application of non-viral vectors in mainstream medicine, such as efficiency, biocompatibility, long-lasting effect, route of administration, design of experimental condition or commercialization process. In addition, potential strategies for overcoming main hurdles are also addressed. Overall, this review aims to raise awareness among the scientific community and help researchers gain knowledge in the design of safe and efficient non-viral gene delivery systems for clinical applications to progress in the gene therapy field.

scholarly journals Characterization of Recombinant Adeno-Associated Viruses (rAAVs) for Gene Therapy Using Orthogonal Techniques

Pharmaceutics ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 586
Author(s):  
Liam Cole ◽  
Diogo Fernandes ◽  
Maryam T. Hussain ◽  
Michael Kaszuba ◽  
John Stenson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Light Scattering ◽  
Dynamic Light Scattering ◽  
Viral Vector ◽  
Structural Characteristics ◽  
Genetic Material ◽  
Label Free ◽  
Gene Therapies ◽  
Multiple Challenges

Viruses are increasingly used as vectors for delivery of genetic material for gene therapy and vaccine applications. Recombinant adeno-associated viruses (rAAVs) are a class of viral vector that is being investigated intensively in the development of gene therapies. To develop efficient rAAV therapies produced through controlled and economical manufacturing processes, multiple challenges need to be addressed starting from viral capsid design through identification of optimal process and formulation conditions to comprehensive quality control. Addressing these challenges requires fit-for-purpose analytics for extensive characterization of rAAV samples including measurements of capsid or particle titer, percentage of full rAAV particles, particle size, aggregate formation, thermal stability, genome release, and capsid charge, all of which may impact critical quality attributes of the final product. Importantly, there is a need for rapid analytical solutions not relying on the use of dedicated reagents and costly reference standards. In this study, we evaluate the capabilities of dynamic light scattering, multiangle dynamic light scattering, and SEC–MALS for analyses of rAAV5 samples in a broad range of viral concentrations (titers) at different levels of genome loading, sample heterogeneity, and sample conditions. The study shows that DLS and MADLS® can be used to determine the size of full and empty rAAV5 (27 ± 0.3 and 33 ± 0.4 nm, respectively). A linear range for rAAV5 size and titer determination with MADLS was established to be 4.4 × 1011–8.7 × 1013 cp/mL for the nominally full rAAV5 samples and 3.4 × 1011–7 × 1013 cp/mL for the nominally empty rAAV5 samples with 3–8% and 10–37% CV for the full and empty rAAV5 samples, respectively. The structural stability and viral load release were also inferred from a combination of DLS, SEC–MALS, and DSC. The structural characteristics of the rAAV5 start to change from 40 °C onward, with increasing aggregation observed. With this study, we explored and demonstrated the applicability and value of orthogonal and complementary label-free technologies for enhanced serotype-independent characterization of key properties and stability profiles of rAAV5 samples.

Inhibition of glioma by adenovirus KGHV500 encoding anti-p21Ras scFv and carried by cytokine-induced killer cells

2021 ◽  
pp. 153537022098676
Author(s):  
Jing Qian ◽  
Mo Yang ◽  
Qiang Feng ◽  
Xin-Yan Pan ◽  
Li-Lin Yang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Glioma Cell ◽  
Therapeutic Strategy ◽  
Recombinant Adenovirus ◽  
Mapk Pathway ◽  
Control Treatment ◽  
Proliferation Index ◽  
Ras Gene ◽  
Cik Cells ◽  
Anti Tumor Activity

Ras gene mutation or overexpression can lead to tumorigenesis in multiple kinds of cancer, including glioma. However, no drugs targeting Ras or its expression products have been approved for clinical application thus far. Adenoviral gene therapy is a promising method for the treatment of glioma. In this study, the human glioma cell line U251 was co-cultured with recombinant adenovirus KGHV500, and the anti-tumor effects of KGHV500 were determined by MTT, scratch test, Transwell invasion, and apoptosis assays. Then, KGHV500 was delivered via the intravenous injection of CIK cells into glioma xenografts. Tumor volume, ki67 proliferation index, apoptosis levels, and anti-p21Ras scFv expression were tested to evaluate targeting ability, anti-tumor efficacy, and safety. We found that the KGHV500 exhibited anti-tumor activity in U251 cells and increased the intracellular expression of anti-p21Ras scFv compared with that in the control groups. CIK cells delivered KGHV500 to U251 glioma cell xenografts and enhanced anti-tumor activity against glioma xenografts compared to that produced by the control treatment. In conclusion, targeting Ras is a useful therapeutic strategy for gliomas and other Ras-driven cancers, and the delivery of anti-p21Ras scFv by recombinant adenovirus and CIK cells may play an essential role in the therapy of Ras-driven cancers. Impact statement For glioma treatment, gene therapy/virotherapy approach is a promising candidate. The Ras gene is reported to play a vital role in the RAS/RAF/mitogen-activated protein kinase (MAPK) pathway in gliomas. Thus, targeting the Ras gene should be a reasonable potential therapeutic method for glioma. In the present study, we used cytokine-induced killer (CIK) cells as secondary vectors to systemically deliver recombinant adenovirus KGHV500 to glioma xenografts and investigated the anti-tumor efficiency of recombinant adenovirus KGHV500 in vitro and in vivo. Our results expand evidence that targeting Ras is a useful and potential therapeutic strategy for gliomas. We believe that anti-p21Ras scFv delivered by recombinant adenovirus and CIK cells may play an important role in the therapy of Ras-driven cancers.

Potential strategies for cancer gene therapy

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Gene Therapy ◽  
Clinical Stage ◽  
Genetic Material ◽  
Direct Methods ◽  
Cancer Gene Therapy ◽  
Target Cells ◽  
Target Tissue ◽  
Cancer Gene ◽  
P Gene

Gene therapy involves transferring genetic material (DNA or RNA) to repair, regulate or replace genes to cure a disease. One of the most crucial barriers is successful delivery of the targeted gene into the target tissue. Various vector-based approaches have been developed to deliver the transgene to the target cells. In different cancers, numerous of these vectors are being developed for purposes such as immunotherapy, suicide gene therapy, microRNA (miRNA) focused treatment, oncogene silencing, and gene editing using CRISPR/Cas9. This article reviews several alternatives to cancer gene therapy, as well as their preclinical and clinical outcomes, possible limitations, and overall therapy effects. Ways of delivering cancer gene therapy include direct methods for introducing genetic material. Nonviral vectors are easy to manufacture and may be chemically modified to increase their usefulness. Cationic polymers such as Poly-L-Lysine (PLL) and Polyethylenimine (PEI-SS) are the most extensively used polycationic polymers for gene transfer, particularly in vitro. Many RNAi-based therapeutic approaches are approaching the clinical stage, and nanocarriers are likely to play a crucial role in treating specific cancers. In the previous decade, non-viral approaches were used in more than 17 percent of all gene therapy trials. The message is that this is a safe and effective technique for transferring genes to cancer patients who need it to be a safe, successful therapy. Exosomes were developed to carry oncogene-specific short interfering RNA. Sushrut and colleagues revealed that exosomes provide superior carriers of short RNA and prevent tumor growth than liposomes. Inhalation-based gene therapy (aerosol-mediated gene delivery) has gained pace as a feasible treatment approach, especially for lung cancer. Because the intended transgene is steered to specific cells/tissues, this should further increase therapeutic efficiency.

Gene Therapy for Inherited Retinopathies: Update on Development Progress

2018 ◽  
Vol 2 (4) ◽  
pp. 219-226
Author(s):  
Susan Sun ◽  
Sandra R. Montezuma
Keyword(s):  
Gene Therapy ◽  
Genetic Disorders ◽  
Treatment Options ◽  
Genetic Material ◽  
Disease Process ◽  
Supportive Therapy ◽  
The Us ◽  
Retinal Disorders ◽  
The Status ◽  
Therapy Treatment

Inherited retinopathies are a group of genetic disorders that lead to blindness and/or vision impairment. Until now, treatment options for inherited retinopathies largely remained limited to supportive therapy. Gene therapy is an attractive therapeutic technique that allows repair of diseased genes, and it has shown success in vision improvement for patients affected by retinal disorders caused by genetic mutations. The US Food and Drug Administration approved the first gene therapy treatment for the eye, indicated for biallelic RPE65 mutation associated Leber congenital amaurosis (LCA), in December of 2017. Additionally, results from other ongoing clinical trials could further establish gene therapy as the milestone treatment that plays a role in disease process reversal for inherited retinopathies. This review article provides an update on the status of gene therapy for treatment of a variety of retinopathies, including LCA, choroideremia, achromatopsia, Stargardt disease, X-linked retinitis pigmentosa, and X-linked retinoschisis. Furthermore, this article explores transport methods of the genetic material, as well as therapy-delivery approaches used in the clinical setting.

scholarly journals Gene Therapy in the Management of Erectile Dysfunction (ED): Past, Present, and Future

2009 ◽  
Vol 9 ◽  
pp. 846-854 ◽  
Author(s):  
Arnold Melman ◽  
Kelvin P. Davies
Keyword(s):  
Gene Therapy ◽  
Erectile Dysfunction ◽  
Viral Vectors ◽  
Genetic Material ◽  
Phase I Trials ◽  
Clinical Phase ◽  
The Past ◽  
Novel Treatment ◽  
Therapy Treatment ◽  
Gene Transfer Techniques

In the past, many researchers considered viral vectors to be the most promising candidates to transfer genetic material into the corpora for the treatment of erectile dysfunction. However, at present, no viral vectors have progressed to human trials. In contrast, the use of naked gene therapy, a plasmid expressing the human Maxi-K potassium channel, is the only gene therapy treatment to be evaluated in clinical phase I trials to date. The success of these studies, proving the safety of this treatment, has paved the way for the development of future gene transfer techniques based on similar transfer methods, as well as novel treatment vectors, such as stem cell transfer.

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