Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects

Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics

Continued Fractions and Unique Factorization on Digraphs

We show that the characteristic series of walks (paths) between any two vertices of any finite digraph or weighted digraph G is given by a universal continued fraction of finite depth involving the simple paths and simple cycles of G. A simple path is a walk forbidden to visit any vertex more than once. We obtain an explicit formula giving this continued fraction. Our results are based on an equivalent to the fundamental theorem of arithmetic: we demonstrate that arbitrary walks on G uniquely factorize into nesting products of simple paths and simple cycles. Nesting is a walk product which we define. We show that the simple paths and simple cycles are the prime elements of the ensemble of all walks on G equipped with the nesting product. We give an algorithm producing the prime factorization of individual walks. We obtain a recursive formula producing the prime factorization of ensembles of walks. Our results have already found applications in the field of matrix computations. We give examples illustrating our results

An Exact Formulation of the Time-Ordered Exponential using Path-Sums

We present the path-sum formulation for $\mathsf{OE}[\mathsf{H}](t',t)=\mathcal{T}\,\text{exp}\big(\int_{t}^{t'}\!\mathsf{H}(\tau)\,d\tau\big)$, the time-ordered exponential of a time-dependent matrix $\mathsf{H}(t)$. The path-sum formulation gives $\mathsf{OE}[\mathsf{H}]$ as a branched continued fraction of finite depth and breadth. The terms of the path-sum have an elementary interpretation as self-avoiding walks and self-avoiding polygons on a graph. Our result is based on a representation of the time-ordered exponential as the inverse of an operator, the mapping of this inverse to sums of walks on graphs and the algebraic structure of sets of walks. We give examples demonstrating our approach. We establish a super-exponential decay bound for the magnitude of the entries of the time-ordered exponential of sparse matrices. We give explicit results for matrices with commonly encountered sparse structures

An Exact Formulation of the Time-Ordered Exponential using Path-Sums

We present the path-sum formulation for $\mathsf{OE}[\mathsf{H}](t',t)=\mathcal{T}\,\text{exp}\big(\int_{t}^{t'}\!\mathsf{H}(\tau)\,d\tau\big)$, the time-ordered exponential of a time-dependent matrix $\mathsf{H}(t)$. The path-sum formulation gives $\mathsf{OE}[\mathsf{H}]$ as a branched continued fraction of finite depth and breadth. The terms of the path-sum have an elementary interpretation as self-avoiding walks and self-avoiding polygons on a graph. Our result is based on a representation of the time-ordered exponential as the inverse of an operator, the mapping of this inverse to sums of walks on graphs and the algebraic structure of sets of walks. We give examples demonstrating our approach. We establish a super-exponential decay bound for the magnitude of the entries of the time-ordered exponential of sparse matrices. We give explicit results for matrices with commonly encountered sparse structures

Recombinant adeno-associated virus vectors in the treatment of rare diseases

INTRODUCTION: An estimated 25 million Americans are living with rare diseases. Adeno-associated virus (AAV)-mediated gene therapy is an emerging therapeutic option for the more than 7,000 identified rare diseases. This paper highlights the benefits of AAV therapy compared to conventional small molecules, discusses current pre-clinical and clinical applications of AAV-mediated gene therapy, and offers insights into cutting edge research that will shape the future of AAV for broad therapeutic use. AREAS COVERED: In this review the biology of AAV and our ability to generate disease-specific variants is summarized. Limitations of current therapy are reviewed, with an emphasis on immune detection of virus, viral tropism and tissue targeting, and limitations of gene expression. Information for this review was found using PubMed and clinicaltrials.gov. EXPERT OPINION: Currently the scope of clinical trials of AAV gene therapy is concentrated in an array of phase I/II safety trials with less than two dozen rare diseases featured. Pre-clinical, translational studies are expanding in number as developments within the last decade have made generation of improved AAV vectors available to more researchers. Further, one bottleneck that is being overcome is the availability of disease models, which will allow for improved preclinical testing and advancement of AAV to more clinical applications

Clinical and in vitro

Treatment of infections caused by Burkholderia cepacia complex (Bcc) in cystic fibrosis (CF) patients poses a complex problem. Bcc is multidrug-resistant due to innate and acquired mechanisms of resistance. As CF patients receive multiple courses of antibiotics, susceptibility patterns of strains from CF patients may differ from those noted in strains from non-CF patients. Thus, there was a need for assessing in vitro and clinical data to guide antimicrobial therapy in these patients. A systematic search of literature, followed by extraction and analysis of available information from human and in vitro studies was done. The results of the analysis are used to address various aspects like use of antimicrobials for pulmonary and non-pulmonary infections, use of combination versus monotherapy, early eradication, duration of therapy, route of administration, management of biofilms, development of resistance during therapy, pharmacokinetics–pharmacodynamics correlations, therapy in post-transplant patients and newer drugs in Bcc-infected CF patients