Longevity Bottlenecks

Introducing a New ASGCT Forum for Publication of Methodology and Clinical Development in Gene, Cell, and Oligonucleotide Therapies

Gene therapies for genetic diseases have been sought for decades, and the relatively recent development of the CRISPR/Cas9 gene-editing system has encouraged a new wave of interest in the field. There have nonetheless been significant setbacks to gene therapy, including unintended biological consequences, ethical scandals, and death. The major focus of research has been on technological problems such as delivery, potential immune responses, and both on and off-target effects in an effort to avoid negative clinical outcomes. While the field has concentrated on how we can better achieve gene therapies and gene editing techniques, there has been less focus on when and why we should use such technology. Here we combine discussion of both the technical and ethical barriers to the widespread clinical application of gene therapy and gene editing, providing a resource for gene therapy experts and novices alike. We discuss ethical problems and solutions, using cystic fibrosis and beta-thalassemia as case studies where gene therapy might be suitable, and provide examples of situations where human germline gene editing may be ethically permissible. Using such examples, we propose criteria to guide researchers and clinicians in deciding whether or not to pursue gene therapy as a treatment. Finally, we summarize how current progress in the field adheres to principles of biomedical ethics and highlight how this approach might fall short of ethical rigour using examples in the bioethics literature. Ultimately by addressing both the technical and ethical aspects of gene therapy and editing, new frameworks can be developed for the fair application of these potentially life-saving treatments.

Gene and Cell Therapy Funding Opportunities in Horizon 2020: An Overview for 2014–2015

Understanding the “code of life” and mapping the human genome have been monumental and era-defining scientific landmarks—analogous to setting foot on the moon. The last century has been characterized by exponential advances in our understanding of the biological and specifically molecular basis of health and disease. The early part of the 20th century was marked by fundamental theoretical and scientific advances in understanding heredity, the identification of the DNA molecule and genes, and the elucidation of the central dogma of biology. The second half was characterized by experimental and increasingly molecular investigations, including clinical and population applications. The completion of the Human Genome Project in 2003 and the continuous technological advances have democratized access to this information and the ability to generate health and disease association data; however, the realization of genomic and precision medicine, to practically improve people’s health, has lagged. The oral health domain has made great strides and substantially benefited from the last century of advances in genetics and genomics. Observations regarding a hereditary component of dental caries were reported as early as the 1920s. Subsequent breakthroughs were made in the discovery of genetic causes of rare diseases, such as ectodermal dysplasias, orofacial clefts, and other craniofacial and dental anomalies. More recently, genome-wide investigations have been conducted and reported for several diseases and traits, including periodontal disease, dental caries, tooth agenesis, cancers of the head and neck, orofacial pain, temporomandibular disorders, and craniofacial morphometrics. Gene therapies and gene editing with CRISPR/Cas represent the latest frontier surpassed in the era of genomic medicine. Amid rapid genomics progress, several challenges and opportunities lie ahead. Importantly, systematic efforts supported by implementation science are needed to realize the full potential of genomics, including the improvement of public and practitioner genomics literacy, the promotion of individual and population oral health, and the reduction of disparities.

Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver-directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver-targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler-Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow-up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver-targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.

U.S. Regulatory Challenges for Gene Editing

Chapter 24 - “Gene therapy”: ethical and regulatory issues

This work represents a retrospective and updated review in a scientific context of itself, the Advanced Therapies group of the Complutense University of Madrid. The project, which began almost 7 years ago, has pursued the establishment of gene and cell therapy protocols for the treatment of coagulation factor V deficiency. This “trip” has been possible thanks to the Association for the Research and Cure of Factor V Deficiency, A Hope for Celia, through micro sponsorship or crowdfunding and through predoctoral contracts granted by the Complutense University of Madrid. The results obtained and presented in the present work have been very successful for this ultra-rare disease. The project was initiated with the complete study of the mutational cause in a patient (Celia) and the study of her progenitor segregation; then, with the establishment of cellular and live animal models for the pathological mutation, using gene editing with CRISPR, the measurement of factor V in mice was standardized, and finally, the proof of concept of a gene therapy lentiviral protocol was demonstrated. All these results have given rise to several articles published in high-impact journals and two that are in the process of editorial review. Two patents have also been obtained on the correction of mutations in the F5 gene by gene editing and another on the viable animal model itself with factor V deficiency. All these results open the door to future approaches in the preclinical phase in animal models to establish the guarantees of efficacy and safety of the gene therapy protocol with lentiviral vectors. Keywords: Hemostasis and factor V deficiency; rare diseases; cellular and animal models of pathology; advanced therapies; gene therapy; CRISPR gene editing

In this issue of Circulation , Baumgartner et al1 ). The plasmid DNA was injected directly into the muscle of ischemic limbs. Anatomic and functional efficacy was demonstrated by increased serum levels of VEGF, improved hemodynamic measurements and angiographic evaluation, reduced pain, increased healing of ischemic ulcers, limb salvage, and immunohistochemical evidence of proliferating endothelial cells in tissue specimens. The authors emphasize that this is the first medical therapy to achieve an increase in limb perfusion that is equivalent to or greater than successful surgical or percutaneous intervention. Direct intramuscular gene transfer of plasmid DNA appears to effectively stimulate collateral vessel growth, despite the lower transfection efficiency that is usually associated with gene therapy in the absence of a viral vector. This result has implications for other clinical trials of gene therapy that use intramuscular naked DNA. The fact that Isner’s group could prepare the plasmid for human use in a university medical center laboratory dedicated to this purpose reveals why gene therapy has moved so rapidly from the laboratory to the clinic, in contrast to protein therapy, which requires expensive manufacturing facilities and years of scale-up effort. Although the plasmid was injected into muscle of the ischemic limb, VEGF levels were apparently elevated in the whole circulation, as evidenced by transient peaks of VEGF in the serum and by edema of the ischemic limb and in some patients, in the opposite limb. The increased collateral vessels, however, are localized to the ischemic limb and do not develop in other areas of the body. This may reflect in part the short half-life of VEGF in the circulation (minutes) as well as the upregulation of receptors for VEGF in ischemic tissue. …

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In Vivo RNA delivery by targeted lipid nanoparticles enable gene editing in hematopoietic stem cells and T cells

There are few sources from which to obtain clinical and genetic data for use in research in Saudi Arabia. Numerous obstacles led to the difficulty of integrating these data from silos and scattered sources to provide standardized access to large data sets for patients with common health conditions. To this end, we sought to contribute to this area and offer a practical and easy-to-implement solution. In this paper, we aim to design and implement a “not only SQL” (NoSQL) based integration framework to generate an Integrated Data Repository of Genetic Disorders Data (GENE2D) to integrate data from various genetic clinics and research centers in Saudi Arabia and provide an easy-to-use query interface for researchers to conduct their studies on large datasets. The major components involved in the GENE2D architecture consists of the data sources, the integrated data repository (IDR) as a central database, and the application interface. The IDR uses a NoSQL document store via MongoDB (an open source document-oriented database program) as a backend database. The application interface called Query Builder provides multiple services for data retrieval from the database using a custom query to answer simple or complex research questions. The GENE2D system demonstrates its potential to help grow and develop a national genetic disorders database in Saudi Arabia.

Language interventions are complex behavioural interventions, making it difficult to distinguish the specific factors contributing to efficacy. The efficacy of oral language comprehension interventions varies greatly, but the reasons for this have received little attention. The aim of this meta-analysis was to examine which intervention factors are associated with efficacy (as expressed with effect sizes) regarding interventions aiming to improve oral language comprehension on its own, or together with expressive language, in children under the age of 18 with or at risk for (developmental) language disorder-(D)LD. Whether the interventions for younger and older children differ from one another regarding efficacy or factors possibly associated with efficacy were also examined. Studies (n = 46) were identified through two systematic scoping reviews. Factors associated with efficacy were categorized according to the internal characteristics of the intervention as well as factors external to the intervention. Statistical analyses were conducted to examine the association between these factors and intervention efficacy as represented by effect sizes on oral language comprehension outcome measures. Targeting language, language environment or compensatory strategies indicated efficacy, whereas aiming to improve language processing indicated no clinically significant efficacy. Targeting only receptive language was associated with larger effect sizes than targeting both receptive and expressive language. The interventions for younger (2-7 years) and older (8-13 years) children indicated a similar degree of efficacy, but the way in which these results were achieved varied, as comprehension interventions for younger and older children differed from one another. Many factors associated with effect sizes were also associated with each other making interpretation of the results complex. These indicative results suggest that it is not reasonable to target language processing, such as auditory processing or automatization, when aiming to improve oral language comprehension. Targeting receptive language only rather than both receptive and expressive language seems preferable to maximize efficacy when aiming to support solely oral language comprehension instead of targeting both expression and comprehension. The qualitative active ingredients of treatment appear to be more important than the number of intervention hours. Although children of different ages can benefit from interventions to enhance oral language comprehension, the child's age needs to be carefully considered to develop interventions that are optimal. Further research with larger data sets regarding factors contributing to efficacy is still needed before applying these results confidently to clinical practice. What is already known on this subject Little is known about the specific intervention factors associated with efficacy of comprehension interventions, and whether these differ between children of different ages. To be able to choose and create optimal comprehension interventions, a better understanding of the mechanisms of change is needed. What this paper adds to the existing knowledge The results indicate that oral comprehension skills of children aged 2-13 years with or at risk for (D)LD can be supported. Targeting language processing, such as auditory processing or automatization, does not seem reasonable when aiming to support oral comprehension. Rather, the interventions should target children's language skills related to comprehension, their language environment or provide children with compensatory strategies. The types of interventions used with younger and older children differed, such that those used with older children were more targeted, adult-directed, applied in formal activities, as well as used taught strategies and more explicit methods of instruction. What are the potential or actual clinical implications of this work? When developing interventions for oral language comprehension, the child's age needs to be considered. Further, what is targeted in an intervention in relation to the aim of the intervention needs careful consideration. The content of the intervention (therapeutic dose form) appears to have precedence over the amount of intervention.

Nanobiomaterial vectors for improving gene editing and gene therapy

Safety and feasibility of various fasting-mimicking diets among people with multiple sclerosis