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Systematic Review of the Preclinical Technology Readiness of Orthopedic Gene Therapy and Outlook for Clinical Translation.

ABSTRACT: Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has been proposed as a possible approach to improve or augment bone healing with the potential to provide true functional regeneration. While large numbers of studies have been performed in vitro or in vivo in small animal models that support the use of gene therapy for bone repair, these systems do not recapitulate several key features of a critical or complex fracture environment. Larger animal models are therefore a key step on the path to clinical translation of the technology. Herein, the current state of orthopedic gene therapy research in preclinical large animal models was investigated based on performed large animal studies. A summary and an outlook regarding current clinical studies in this sector are provided. It was found that the results found in the current research literature were generally positive but highly methodologically inconsistent, rendering a comparison difficult. Additionally, factors vital for translation have not been thoroughly addressed in these model systems, and the risk of bias was high in all reviewed publications. These limitations directly impact clinical translation of gene therapeutic approaches due to lack of comparability, inability to demonstrate non-inferiority or equivalence compared with current clinical standards, and lack of safety data. This review therefore aims to provide a current overview of ongoing preclinical and clinical work, potential bottlenecks in preclinical studies and for translation, and recommendations to overcome these to enable future deployment of this promising technology to the clinical setting.

SUBMITTER: Wilkinson P

PROVIDER: S-EPMC8011540 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThe translation of research into practices has been incomplete. Organizational readiness for change (ORC) is a potential facilitator of effective knowledge translation (KT). However we know little about the best way to assess ORC. Therefore, we sought to systematically review ORC measurement instruments.MethodsWe searched for published studies in bibliographic databases (Pubmed, Embase, CINAHL, PsychINFO, Web of Science, etc.) up to November 1st, 2012. We included publications that developed ORC measures and/or empirically assessed ORC using an instrument at the organizational level in the health care context. We excluded articles if they did not refer specifically to ORC, did not concern the health care domain or were limited to individual-level change readiness. We focused on identifying the psychometric properties of instruments that were developed to assess readiness in an organization prior to implementing KT interventions in health care. We used the Standards for Educational and Psychological Testing to assess the psychometric properties of identified ORC measurement instruments.FindingsWe found 26 eligible instruments described in 39 publications. According to the Standards for Educational and Psychological Testing, 18 (69%) of a total of 26 measurement instruments presented both validity and reliability criteria. The Texas Christian University -ORC (TCU-ORC) scale reported the highest instrument validity with a score of 4 out of 4. Only one instrument, namely the Modified Texas Christian University - Director version (TCU-ORC-D), reported a reliability score of 2 out of 3. No information was provided regarding the reliability and validity of five (19%) instruments.ConclusionOur findings indicate that there are few valid and reliable ORC measurement instruments that could be applied to KT in the health care sector. The TCU-ORC instrument presents the best evidence in terms of validity testing. Future studies using this instrument could provide more knowledge on its relevance to diverse clinical contexts.

Project description:BackgroundMeniscus damage can be caused by trauma or degeneration and is therefore common among patients of all ages. Repair or regeneration of the menisci could be of great importance not only for pain relief or regaining function but also to prevent degenerative disease and osteoarthritis. Current treatment does not offer consistent long-term improvement. Although preclinical research focusing on augmentation of meniscal tear repair and regeneration after meniscectomy is encouraging, clinical translation remains difficult.PurposeTo systematically evaluate the literature on in vivo meniscus regeneration and explore the optimal cell sources and conditions for clinical translation. We aimed at thorough evaluation of current evidence as well as clarifying the challenges for future preclinical and clinical studies.Study designSystematic review.MethodsA search was conducted using the electronic databases of MEDLINE, Embase, and the Cochrane Collaboration. Search terms included meniscus, regeneration, and cell-based.ResultsAfter screening 81 articles based on title and abstract, 51 articles on in vivo meniscus regeneration could be included; 2 additional articles were identified from the references. Repair and regeneration of the meniscus has been described by intra-articular injection of multipotent mesenchymal stromal (stem) cells from adipose tissue, bone marrow, synovium, or meniscus or the use of these cell types in combination with implantable or injectable scaffolds. The use of fibrochondrocytes, chondrocytes, and transfected myoblasts for meniscus repair and regeneration is limited to the combination with different scaffolds. The comparative in vitro and in vivo studies mentioned in this review indicate that the use of allogeneic cells is as successful as the use of autologous cells. In addition, the implantation or injection of cell-seeded scaffolds increased tissue regeneration and led to better structural organization compared with scaffold implantation or injection of a scaffold alone. None of the studies mentioned in this review compare the effectiveness of different (cell-seeded) scaffolds.ConclusionThere is heterogeneity in animal models, cell types, and scaffolds used, and limited comparative studies are available. The comparative in vivo research that is currently available is insufficient to draw strong conclusions as to which cell type is the most promising. However, there is a vast amount of in vivo research on the use of different types of multipotent mesenchymal stromal (stem) cells in different experimental settings, and good results are reported in terms of tissue formation. None of these studies compare the effectiveness of different cell-scaffold combinations, making it hard to conclude which scaffold has the greatest potential.

Project description:INTRODUCION:With the increasing number of children exposed to HIV or antiretroviral therapy in utero, there are concerns that this population may have worse neurodevelopmental outcomes compared to those who are unexposed. The objective of this study was to systematically review the clinical and preclinical literature on the effects of in utero exposure to HIV and/or antiretroviral therapy (ART) on neurodevelopment. METHODS:We systematically searched OVID Medline, PsycINFO and Embase, as well as the Cochrane Collaborative Database, Google Scholar and bibliographies of pertinent articles. Titles, abstracts, and full texts were assessed independently by two reviewers. Data from included studies were extracted. Results are summarized qualitatively. RESULTS:The search yielded 3027 unique titles. Of the 255 critically reviewed full-text articles, 25 met inclusion criteria for the systematic review. Five articles studied human subjects and looked at brain structure and function. The remaining 20 articles were preclinical studies that mostly focused on behavioural assessments in animal models. The few clinical studies had mixed results. Some clinical studies found no difference in white matter while others noted higher fractional anisotropy and lower mean diffusivity in the brains of HIV-exposed uninfected children compared to HIV-unexposed uninfected children, correlating with abnormal neurobehavioral scores. Preclinical studies focused primarily on neurobehavioral changes resulting from monotherapy with either zidovudine or lamivudine. Various developmental and behavioural changes were noted in preclinical studies with ART exposure, including decreased grooming, decreased attention, memory deficits and fewer behaviours associated with appropriate social interaction. CONCLUSIONS:While the existing literature suggests that there may be some neurobehavioral differences associated with HIV and ART exposure, limited data are available to substantially support these claims. More research is needed comparing neurobiological factors between HIV-exposed uninfected and HIV-unexposed uninfected children and using exposures consistent with current clinical care.

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Systematic Review of the Preclinical Technology Readiness of Orthopedic Gene Therapy and Outlook for Clinical Translation.

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