scholarly journals Taking Gene Therapy into the Clinic

2003 ◽  
Vol 2003 (1) ◽  
pp. 71-77 ◽  
Author(s):  
Daniel H. Palmer ◽  
Ming-Jen Chen ◽  
David J. Kerr
Keyword(s):  
Colorectal Cancer ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Gene Targeting ◽  
Treatment Strategy ◽  
Phase 1 ◽  
Therapeutic Benefit ◽  
Cancer Treatments ◽  
Novel Treatment

Gene therapy represents a promising novel treatment strategy for colorectal cancer. Preclinical data has been encouraging and several clinical trials are underway. Many phase 1 trials have proven the safety of the reagents but have yet to demonstrate significant therapeutic benefit. Ongoing efforts are being made to improve the efficiency of gene delivery and accuracy of gene targeting with the aim of enhancing antitumor potency. It is envisaged that gene therapy will be used in combination with other therapies including surgery, chemotherapy, and radiotherapy to facilitate the improvements in cancer treatments in the future.

scholarly journals Enhancement of Muscle Gene Delivery with Pseudotyped Adeno-Associated Virus Type 5 Correlates with Myoblast Differentiation

2001 ◽  
Vol 75 (16) ◽  
pp. 7662-7671 ◽  
Author(s):  
Dongsheng Duan ◽  
Ziying Yan ◽  
Yongping Yue ◽  
Wei Ding ◽  
John F. Engelhardt
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Muscle Cells ◽  
Therapeutic Benefit ◽  
Transduction Efficiency ◽  
Great Promise ◽  
Adeno Associated Virus ◽  
Muscle Gene ◽  
Duchenne's Muscular Dystrophy

ABSTRACT Adeno-associated virus (AAV)-based muscle gene therapy has achieved tremendous success in numerous animal models of human diseases. Recent clinical trials with this vector have also demonstrated great promise. However, to achieve therapeutic benefit in patients, large inocula of virus will likely be necessary to establish the required level of transgene expression. For these reasons, efforts aimed at increasing the efficacy of AAV-mediated gene delivery to muscle have the potential for improving the safety and therapeutic benefit in clinical trials. In the present study, we compared the efficiency of gene delivery to mouse muscle cells for recombinant AAV type 2 (rAAV-2) and rAAV-2cap5 (AAV-2 genomes pseudo-packaged into AAV-5 capsids). Despite similar levels of transduction by these two vectors in undifferentiated myoblasts, pseudotyped rAAV-2cap5 demonstrated dramatically enhanced transduction in differentiated myocytes in vitro (>500-fold) and in skeletal muscle in vivo (>200-fold) compared to rAAV-2. Serotype-specific differences in transduction efficiency did not directly correlate with viral binding to muscle cells but rather appeared to involve endocytic or intracellular barriers to infection. Furthermore, application of this pseudotyped virus in a mouse model of Duchenne's muscular dystrophy also demonstrated significantly improved transduction efficiency. These findings should have a significant impact on improving rAAV-mediated gene therapy in muscle.

scholarly journals Transcriptional Targeting in Cancer Gene Therapy

2003 ◽  
Vol 2003 (2) ◽  
pp. 110-137 ◽  
Author(s):  
Tracy Robson ◽  
David G. Hirst
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Cancer Gene Therapy ◽  
Cancer Gene ◽  
Cancer Treatments ◽  
Transcriptional Targeting ◽  
Exogenous Agents ◽  
Therapeutic Research ◽  
Systemic Gene Delivery ◽  
Near Future

Cancer gene therapy has been one of the most exciting areas of therapeutic research in the past decade. In this review, we discuss strategies to restrict transcription of transgenes to tumour cells. A range of promoters which are tissue-specific, tumour-specific, or inducible by exogenous agents are presented. Transcriptional targeting should prevent normal tissue toxicities associated with other cancer treatments, such as radiation and chemotherapy. In addition, the specificity of these strategies should provide improved targeting of metastatic tumours following systemic gene delivery. Rapid progress in the ability to specifically control transgenes will allow systemic gene delivery for cancer therapy to become a real possibility in the near future.

Exceptional responses in patients with metastatic colorectal cancer enrolled in first-in-man studies from 2002 through 2012.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 687-687
Author(s):  
Shiven B. Patel ◽  
Danielle Tometich ◽  
Zachary L Reese ◽  
Sunil Sharma ◽  
Ignacio Garrido-Laguna
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Complete Response ◽  
Response To Therapy ◽  
Search Term ◽  
Tumor Type ◽  
Gamma Secretase

687 Background: Understanding exceptional responses to therapy at the molecular level may open new venues for the treatment of patients with metastatic colorectal cancer (mCRC). Responses in first-in-man (FIM) studies with targeted therapies are rare and may indicate that actionable genetic aberrations are present in these patients. Methods: We utilized Scopus using the search term “phase 1 and solid tumors” to collect all FIM studies published between 2002 and 2012. We identified patients with mCRC who attained an exceptional response to therapy defined as a complete response (CR) or a partial response (PR) lasting > 6 months (m). Results: We identified 118 FIM studies enrolling 5,369 patients with advanced malignancies. mCRC was the most common tumor type, totaling 1,055 (19.6%) patients. Of these, two patients enrolled in protocols with MDX-1106 (anti PD-1) and RG7180 (mAb EGFR) attained a complete response (CR). Five patients had PR lasting > 6 m. These patients were treated with RG7180 (time on study 7.8 m), Apatinib, a VEGFR tyrosine kinase inhibitor (8.5 and 7.1 m), PV701, a replication-competent oncolytic virus (10 m) and RO4929097, a gamma-secretase inhibitor (7 m). In addition two patients had PR lasting < 6 m with regorafenib (5.3 m) and RG7180 (5.6 m). This database of exceptional responders to therapy will be publicly available at Huntsman Cancer Institute website. Currently, regorafenib and EGFR mAbs (cetuximab and panitumumab) are approved for use in mCRC. EGFR mAbs have shown improvement in survival in RAS wild-type mCRC. Clinical trials are underway evaluating apatinib. Anti-PD1s have shown limited activity as single agents in mCRC and are currently undergoing testing in combination with chemotherapy. Conclusions: We identified exceptional responses among patients with mCRC enrolled in FIM in the last decade. Ongoing efforts are directed to conduct next generation sequencing (NGS) in archived tissue from these patients. Ultimately, this initiative may facilitate the identification of biomarkers of response to be tested in clinical trials with these or novel drugs sharing similar mechanisms of action.

scholarly journals The Degenerating Substantia Nigra as a Susceptible Region for Gene Transfer-Mediated Inflammation

2011 ◽  
Vol 2011 ◽  
pp. 1-8
Author(s):  
Valeria Roca ◽  
Juan Cruz Casabona ◽  
Pablo Radice ◽  
Verónica Murta ◽  
Fernando Juan Pitossi
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Substantia Nigra ◽  
Neurodegenerative Disorder ◽  
Substantia Nigra Pars Compacta ◽  
Putative Gene ◽  
Inflammatory Stimuli ◽  
Therapy Interventions

Parkinson's disease (PD) is characterized by the progressive degeneration of neurons in the substantia nigra pars compacta (SN). The naïve SN is highly susceptible to inflammation. In addition, microglial activation in the degenerating SN displays distinct characteristics that increase the reactivity of the region towards inflammatory stimuli. On the other hand, gene therapy for PD has recently move forward into clinical settings, with PD being the neurodegenerative disorder with the highest number of Phase I/II gene therapy clinical trials approved and completed. These clinical trials are not targeting the SN, but this region is a certain candidate for future gene therapy interventions. Here, the unique immune-related properties of the degenerating SN in the context of a putative gene therapy intervention are reviewed. Several variables affecting the host response to gene delivery such as vector type and dosage, age and stage of disease of patients, and method of gene delivery and transgene used are discussed. Finally, approaches to diminish the risk of immune-mediated toxicity by gene transfer in the SN are presented.

Left Versus Right: Does Location Matter for Refractory Metastatic Colorectal Cancer Patients in Phase 1 Clinical Trials?

2017 ◽  
Vol 49 (3) ◽  
pp. 283-287 ◽  
Author(s):  
Sukeshi Patel Arora ◽  
Norma S. Ketchum ◽  
Joel Michalek ◽  
Jonathon Gelfond ◽  
Devalingam Mahalingam
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Phase 1 ◽  
Colorectal Cancer Patients

scholarly journals Alzheimer’s disease: An overview of the current treatments

Bionatura ◽  
2019 ◽  
Vol 02 (Bionatura Conference Serie) ◽  
Author(s):  
Carolina Serrano-Larrea ◽  
David Clavijo-Calderón
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Nerve Growth Factor ◽  
Phase 1 ◽  
Phase 2 ◽  
Adeno Associated Virus ◽  
The World ◽  
Phase 2 Clinical Trials

Alzheimer’s disease (AD) affects millions of people around the world and although there are treatments that help control symptoms and slow down the progress of the disease, there is still no cure. Current treatments include three acetylcholine inhibitors, a glutamate inhibitor and a combination of the two. Due to the failure of hundreds of clinical trials with monotherapies, multitarget treatments are currently being investigated that consider both brain and peripheral factors. Gene therapy is one of the most promising therapies to treat and prevent the development of AD. Nowadays, there is no available medical treatment based on gene therapy to treat AD; however, there are treatments in phase 1 and phase 2 clinical trials with promising results. In this review, we will focus on the most important gene therapy treatments, CERE-110 (adeno-associated virus AAV2-Nerve Growth Factor), Intracerebral AAV gene delivery of APOE2 and gene therapy using PPARγ-coactivator-1α(PGC-1α)

The combination of unique biomolecules and nanoparticles has shown successful gene therapy treatment approaches for non-small cell lung cancer treatment

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Lung Cancer ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Cancer Treatment ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Therapeutic Efficacy ◽  
Small Cell ◽  
Small Cell Lung

Using nanotechnology-based drug delivery systems can solve some of the drawbacks of conventional cancer treatment, such as non-specific targeting, solubility difficulties, and poor entry of chemotherapeutic drugs into cancer cells. Over the last two decades, a combination of unique biomolecules and nanoparticles has shown successful treatment approaches for Non-small cell lung cancer (NSCLC) treatment. Targeted gene delivery employing lipid, polymer or metal-based nanoparticles showed positive in vivo and in vitro experimental findings with therapeutic efficacy. Gene therapy has shown enhanced transfection efficiency and targeting potential for various NSCLC cell lines when delivered locally or systemically. Despite this, there are a number of barriers to nanoparticle-mediated gene therapy, including ensuring the stability of biomolecules and nanoparticles during delivery, managing their biodistribution, and reducing the possible adverse effects of nanoparticles. These difficulties must be handled before clinical trials begin. Evaluation of therapeutic efficacy as well as inspection criteria for nanoparticles in gene therapy must be devised to widen the use of nano-gene therapy in cancer treatment. Advanced models, algorithms, and simulations to anticipate nanoparticles' biodistribution, design, and kinetics will be needed in the future to decrease the barrier to nanoparticles in clinical trials. Using new technologies and software, nanoparticles with increased selectivity, increased loading capacity, long circulation periods and effective influx into the vascular endothelium and the blood brain barrier may be generated. Nanoparticles having advanced qualities such as biodegradability, non-toxicity, and non-immunogenicity will facilitate the application of nanotechnology in gene therapy, leading to breakthroughs for cancer patients and in biomedical research. Formulation of unique techniques, notably using a combination of anticancer drugs, must be further researched for effective gene delivery-based therapies.

Cardiac disease: Current approaches to gene therapy

2020 ◽  
pp. 62-75
Author(s):  
Reyad ul-ferdous ◽  
◽  
Shofiul Azam ◽  
◽  
◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Cardiac Disease ◽  
Target Genes ◽  
Viral Vector ◽  
Delivery Methods ◽  
Gene Therapies ◽  
Inherited Cardiomyopathies

Background: Last decade over the world, the cardiac disease becomes a leading cause of death. Gene-based therapies become a promising treatment for patients affected by cardiovascular diseases, such as myocardial infarction (MI), arteriosclerosis, heart failure and so on, but also underline the require for reproducible results in preclinical and clinical studies for efficacy and safety. Aim: This book chapter describes the current research prospect of gene therapy for cardiac disease. We focus on the various models to deliver genes using viral, non-viral vector, delivery methods, targets gene, recent clinical trials, inherited cardiomyopathies target genes and Present advances of CRISPR/Cas 9 for cardiovascular gene therapy. We recapitulate some challenges that require being overcome, future directions of gene therapies for cardiac disease. Materials and Methods: All required information regards Lef-7 was generated by exploring the internet search engine like as (PubMed, Wiley, ScienceDirect, CNKI, ACS, Google Scholar, Web of Science, SciFinder, and Baidu Scholar) and libraries. Results: In this book chapter, we focus on the present prospect of gene targets, gene delivery methods, and efficient vector to deliver gene, targets gene, recent clinical trials, inherited cardiomyopathies target genes and present advances of CRISPR/Cas 9 technology for the treatment of cardiac disease using gene therapy. Recent clinical trials require modifying vectors and gene delivery approaches to achieve effective results for cardiac gene therapy. Conclusion: In this book chapter, we integrate a historical perspective with recent advances that will likely affect clinical development in this research area.

The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2606-2606
Author(s):  
Jason John Luke ◽  
Larry Rubinstein ◽  
Gary L Smith ◽  
S. Percy Ivy ◽  
Pamela Jo Harris
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase 1 ◽  
Therapeutic Benefit ◽  
Phase Iii ◽  
Phase I Trials ◽  
Toxicity Data ◽  
Phase I Clinical Trials ◽  
Exact Test ◽  
Phase Iii Clinical Trials

2606 Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). Many physicians do not refer to phase I due to perceived limited clinical benefit (CB=CR+PR+SD) and increased toxicity. To understand the actual experience of melanoma patients (pts) in phase I trials, we analyzed the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-2011) and compared them to DTIC. Methods: We queried the CTMS of CTEP for phase I trials in which advanced melanoma pts were treated. Trials were separated into targeted (T), chemo (C) and immunotherapy (I). Pt characteristics, response and toxicity data were collected. Chemotherapy included chemo with targeted or immunotherapy. Toxicity was drug related if attributed possibly, probably or definitely to drug. Fisher’s Exact Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 modern phase III clinical trials (1999-2011). Results: 937 pts (M595:F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 (majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and toxicity data are shown in the Table. Targeted therapy was associated with lower RR (p=.01), immuno with lower CB rate (p<.001) and chemo with higher incidence of G4 toxicity (p<.001) relative to the other groups. Comparing phase 1 to DTIC, RR and CB were not clinically different (phase I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was significantly higher (54% vs. 28%) in phase I (p<.0001). Conclusions: Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had similar therapeutic benefit but more toxicity compared to DTIC naïve pts in modern clinical trials. [Table: see text]

For the treatment of cystic fibrosis, RNA medicines, gene transfer therapies, and gene editing treatments have potential

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Cystic Fibrosis ◽  
Gene Therapy ◽  
Clinical Trials ◽  
Acid Treatment ◽  
Gene Editing ◽  
Healthy Adult ◽  
Phase 1 ◽  
Clinical Settings ◽  
Potential Harm ◽  
Cohesive Group

Many unique genetic procedures have been created to reach the heart of the cystic fibrosis (CF) problem, overcoming a defective gene, and advances in the nucleic acid treatment industry have made these methods much more viable as potential remedies. However, before any of these approaches can be used in clinical settings, a number of hurdles must be overcome, including determining which organs should be targeted for the most robust effect with the least amount of potential harm; determining which cells should be targeted in each organ; and determining what constitutes a successful treatment. Another factor to consider is that, unlike many other treatments, gene therapy and gene editing will need advancing clinical trials ahead without data from healthy adult control cohorts; rather, phase 1 studies will require CF patients. Furthermore, we must select which patients should be included in the initial studies for mutation-agnostic methods: should we include all patients, even if effective modulator therapy is available? Clearly, if we are to be successful, we will have to face some significant challenges, and we will have to do it as a cohesive group, as we have always done.

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