An assessment of the factors affecting the commercialization of cell-based therapeutics: a systematic review protocol

Background Cellular-based therapies represent a platform technology within the rapidly expanding field of regenerative medicine and are distinct from conventional therapeutics—offering a unique approach to managing what were once considered untreatable diseases. Despite a significant increase in basic science activity within the cell therapy arena, alongside a growing portfolio of cell therapy trials and promising investment, the translation of cellular-based therapeutics from “bench to bedside” remains challenging, and the number of industry products available for widespread clinical use remains comparatively low. This systematic review identifies unique intrinsic and extrinsic barriers in the cell-based therapy domain. Methods/design Eight electronic databases will be searched, specifically Medline, EMBASE (OvidSP), BIOSIS and Web of Science, Cochrane Library and HEED, EconLit (ProQuest), WHOLIS WHO Library Database, PAIS International (ProQuest), and Scopus. Addition to this gray literature was searched by manually reviewing relevant work. All identified articles will be subjected for review by two authors who will decide whether or not each article passes our inclusion/exclusion criteria. Eligible papers will subsequently be reviewed, and key data extracted into a pre-designed data extraction scorecard. An assessment of the perceived impact of broad commercial barriers to the adoption of cell-based therapies will be conducted. These broad categories will include manufacturing, regulation and intellectual property, reimbursement, clinical trials, clinical adoption, ethics, and business models. This will inform further discussion in the review. There is no PROSPERO registration number. Discussion Through a systematic search and appraisal of available literature, this review will identify key challenges in the commercialization pathway of cellular-based therapeutics and highlights significant barriers impeding successful clinical adoption. This will aid in creating an adaptable, acceptable, and harmonized approach supported by apposite regulatory frameworks and pertinent expertise throughout the respective stages of the adoption cycle to facilitate the adoption of new products and technologies in the industry

Patient-controlled analgesia in the pediatric population: morphine versus hydromorphone

OBJECTIVE: Patient controlled analgesia (PCA) is commonly used to provide analgesia following surgical procedures in the pediatric population. Morphine and hydromorphone remain the most commonly used opioids for PCA. Although both are effective, adverse effects may occur. When these adverse effects are unremitting or severe, opioid rotation may be required. In this study, we retrospectively evaluated PCA use, the adverse effect profile, and the frequency of opioid rotation. METHODS: This retrospective study was performed at Nationwide Children’s Hospital (Columbus, OH). The hospital’s electronic registry was queried for PCA use delivering either morphine or hydromorphone from January 1, 2008 to December 31, 2010. RESULTS: A total of 514 patients were identified, that met study entry criteria. Of the 514 cases, 298 (56.2%) were initially started on morphine and 225 (43.8%) were initially started on hydromorphone. There were a total of 26 (5.1%) opioid changes in the cohort of 514 patients. Of the 26 switches, 23 of 298 (7.7%) were from morphine to hydromorphone, and 3 of 225 (1.3%) were from hydromorphone to morphine (P=0.0008). Of the 17 morphine-to-hydromorphone switches with adverse effects, pruritus (64.7%), and inadequate pain control (47.1%) were the most common side effects. The most common side effect resulting in a hydromorphone-to-morphine switch was nausea (66.7%). CONCLUSION: PCA switches from morphine-to-hydromorphone (88.5%) were more common than vice-versa (11.5%). The most common reasons for morphine-to-hydromorphone switch were pruritus and inadequate pain control. These data suggest that a prospective study is necessary to determine the side effect differences between morphine and hydromorphone in pediatric PCA

Development of β-globin gene correction in human hematopoietic stem cells as a potential durable treatment for sickle cell disease

Sickle cell disease (SCD) is the most common serious monogenic disease with 300,000 births annually worldwide. SCD is an autosomal recessive disease resulting from a single point mutation in codon six of the β-globin gene (HBB). Ex vivo β-globin gene correction in autologous patient-derived hematopoietic stem and progenitor cells (HSPCs) may potentially provide a curative treatment for SCD. We previously developed a CRISPR-Cas9 gene targeting strategy that uses high-fidelity Cas9 precomplexed with chemically modified guide RNAs to induce recombinant adeno-associated virus serotype 6 (rAAV6)-mediated HBB gene correction of the SCD-causing mutation in HSPCs. Here, we demonstrate the preclinical feasibility, efficacy, and toxicology of HBB gene correction in plerixafor-mobilized CD34+ cells from healthy and SCD patient donors (gcHBB-SCD). We achieved up to 60% HBB allelic correction in clinical-scale gcHBB-SCD manufacturing. After transplant into immunodeficient NSG mice, 20% gene correction was achieved with multilineage engraftment. The long-term safety, tumorigenicity, and toxicology study demonstrated no evidence of abnormal hematopoiesis, genotoxicity, or tumorigenicity from the engrafted gcHBB-SCD drug product. Together, these preclinical data support the safety, efficacy, and reproducibility of this gene correction strategy for initiation of a phase 1/2 clinical trial in patients with SCD

RNA-based gene therapy for HIV with lentiviral vector-modified CD34() cells in patients undergoing transplantation for AIDS-related lymphoma

AIDS patients who develop lymphoma are often treated with transplanted hematopoietic progenitor cells. As a first step in developing a hematopoietic cell-based gene therapy treatment, four patients undergoing treatment with these transplanted cells were also given gene-modified peripheral blood-derived (CD34 + ) hematopoietic progenitor cells expressing three RNA-based anti-HIV moieties (tat/rev short hairpin RNA, TAR decoy, and CCR5 ribozyme). In vitro analysis of these gene-modified cells showed no differences in their hematopoietic potential compared with nontransduced cells. In vitro estimates of successful expression of the anti-HIV moieties were initially as high as 22% but declined to~1% over 4 weeks of culture. Ethical study design required that patients be transplanted with both gene-modified and unmanipulated hematopoietic progenitor cells obtained from the patient by apheresis. Transfected cells were successfully engrafted in all four infused patients by day 11, and there were no unexpected infusion-related toxicities. Persistent vector expression in multiple cell lineages was observed at low levels for up to 24 months, as was expression of the introduced small interfering RNA and ribozyme. Therefore, we have demonstrated stable vector expression in human blood cells after transplantation of autologous gene-modified hematopoietic progenitor cells. These results support the development of an RNA-based cell therapy platform for HIV

International Nonregimes: A Research Agenda1

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146934/1/j.1468-2486.2007.00672.x.pd

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Combinatorial RNA-based gene therapy for the treatment of HIV/AIDS

INTRODUCTION: HIV/AIDS continues to be a worldwide health problem and viral eradication has been an elusive goal. HIV+ patients are currently treated with combination antiretroviral therapy (cART) which is not curative. For many patients, cART is inaccessible, intolerable or unaffordable. Therefore a new class of therapeutics for HIV is required to overcome these limitations. Cell and gene therapy for HIV has been proposed as a way to provide a functional cure for HIV in the form of a virus/infection resistant immune system. AREAS COVERED: In this review we describe the standard therapy for HIV/AIDS, its limitations, current areas of investigation and the potential of hematopoietic stem cells modified with anti-HIV RNA as a means to affect a functional cure for HIV. EXPERT OPINION: Cell and gene therapy for HIV/AIDS is a promising alternative to antiviral drug therapy and may provide a functional cure. In order to show clinical benefit, multiple mechanisms of inhibition of HIV entry and lifecycle are likely to be required. Among the most promising anti-viral strategies is the use of transgenic RNA molecules that provide protection from HIV infection. When these molecules are delivered as gene modified hematopoietic stem and progenitor cells, long term repopulation of the patient’s immune system with gene modified progeny has been observed