bims-algemi Biomed News
on Allotopic expression and gene therapy for mitochondrial disease
Issue of 2020‒03‒08
eight papers selected by
Atif Towheed
Columbia University Irving Medical Center


  1. Hum Gene Ther. 2020 Mar 05.
    Tang Y, Yan Z, Engelhardt JF.
      After more than two decades since clinical trials tested the first use of recombinant adeno-associated virus (rAAV) to treat cystic fibrosis (CF) lung disease, gene therapy for this disorder has undergone a tremendous resurgence. Fueling this enthusiasm has been an enhanced understanding of rAAV transduction biology and cellular processes that limit transduction of airway epithelia, the development of new rAAV serotypes and other vector systems with high level tropism for airway epithelial cells, an improved understanding of CF lung pathogenesis and the cellular targets for gene therapy, and the development of new animal models that reproduce the human CF disease phenotype. These advances have created a preclinical path for both assessing the efficacy of gene therapies in the CF lung and interrogating the target cell types in the lung required for complementation of the CF disease state. Lessons learned from early gene therapy attempts with rAAV in the CF lung have guided thinking for the testing of next generation vector systems. Although unknown questions still remain regarding the cellular targets in the lung that are required or sufficient to complement CF lung disease, the field is now well positioned to tackle these challenges. This review will highlight the role next-generation CF animal models are playing in the preclinical development of gene therapies for CF lung disease and the knowledge gaps in disease pathophysiology these models are attempting to fill.
    DOI:  https://doi.org/10.1089/hum.2020.013
  2. Basic Res Cardiol. 2020 Mar 05. 115(3): 23
    Jusic A, Devaux Y, .
      Mitochondrial function and integrity are vital for the maintenance of cellular homeostasis, particularly in high-energy demanding cells. Cardiomyocytes have a large number of mitochondria, which provide a continuous and bulk supply of the ATP necessary for cardiac mechanical function. More than 90% of the ATP consumed by the heart is derived from the mitochondrial oxidative metabolism. Decreased energy supply as the main consequence of mitochondrial dysfunction is closely linked to cardiovascular disease (CVD). The discovery of noncoding RNA (ncRNAs) in the mitochondrial compartment has changed the traditional view of molecular pathways involved in the regulatory network of CVD. Mitochondrial ncRNAs participate in controlling cardiovascular pathogenesis by regulating glycolysis, mitochondrial energy status, and the expression of genes involved in mitochondrial metabolism. Understanding the underlying mechanisms of the association between impaired mitochondrial function resulting from fluctuation in expression levels of ncRNAs and specific disease phenotype can aid in preventing and treating CVD. This review presents an overview of the role of mitochondrial ncRNAs in the complex regulatory network of the cardiovascular pathology. We will summarize and discuss (1) mitochondrial microRNAs (mitomiRs) and long noncoding RNAs (lncRNAs) encoded either by nuclear or mitochondrial genome which are involved in the regulation of mitochondrial metabolism; (2) the role of mitomiRs and lncRNAs in the pathogenesis of several CVD such as hypertension, cardiac hypertrophy, acute myocardial infarction and heart failure; (3) the biomarker and therapeutic potential of mitochondrial ncRNAs in CVD; (4) and the challenges inherent to their translation into clinical application.
    Keywords:  Biomarkers; Cardiovascular disease; Long noncoding RNAs; MicroRNAs; Mitochondria
    DOI:  https://doi.org/10.1007/s00395-020-0783-5
  3. Expert Opin Pharmacother. 2020 Mar 05. 1-11
    Grages SM, Bell M, Berlau DJ.
      Introduction: Duchenne muscular dystrophy (DMD) is the result of X-chromosome-linked mutations to the dystrophin protein gene that prevent the normal development and repair of muscles leading to muscle deterioration. The condition affects nearly 1 in 3,500 males worldwide. Current therapeutics have not been sufficient in providing a cure or resulting in a significant extension in life expectancy, but many therapeutic options are currently under investigation.Areas covered: This article provides an overview of the current and emerging therapies for DMD giving particular focus to synthetic therapeutic options. The authors further provide their expert opinion.Expert opinion: Many discrepancies in primary outcomes of trials have led to questions of efficacy for medications, as well as difficulty in securing FDA approval. A standardization of primary outcome strategies, as well as better access to investigational medications, may alleviate some of the controversy and pressures that exist on medication approvals. Many trials have identified cohorts who responded more favorably to medications, despite a lack of significance in the overall intent-to-treat populations. This indicates that more medication screening and personalized treatment with patient-specific targeting might deliver more clinically significant results.
    Keywords:  Corticosteroids; dystrophin; eteplirsen; exon-skipping; gene therapy; read-through; utrophin
    DOI:  https://doi.org/10.1080/14656566.2020.1732350
  4. NPJ Genom Med. 2020 ;5 7
    Slone J, Huang T.
      The recent success of gene therapy across multiple clinical trials has inspired a great deal of hope regarding the treatment of previously intractable genetic diseases. This optimism has been extended to the prospect of gene therapy for mitochondrial disorders, which are not only particularly severe but also difficult to treat. However, this hope must be tempered by the reality of the mitochondrial organelle, which possesses specific biological properties that complicate genetic manipulation. In this perspective, we will discuss some of these complicating factors, including the unique pathways used to express and import mitochondrial proteins. We will also present some ways in which these challenges can be overcome by genetic manipulation strategies tailored specifically for mitochondrial diseases.
    Keywords:  Diseases; Genetics research; Medical genetics
    DOI:  https://doi.org/10.1038/s41525-020-0116-5
  5. Biochim Biophys Acta Mol Basis Dis. 2020 Feb 28. pii: S0925-4439(20)30097-1. [Epub ahead of print] 165752
    Resende R, Fernandes T, Pereira AC, De Pascale J, Marques AP, Oliveira P, Morais S, Santos V, Madeira N, Pereira C, Moreira PI.
      Mood disorders like major depression and bipolar disorder (BD) are among the most prevalent forms of mental illness. Current knowledge of the neurobiology and pathophysiology of these disorders is still modest and clear biological markers are still missing. Thus, a better understanding of the underlying pathophysiological mechanisms to identify potential therapeutic targets is a prerequisite for the design of new drugs as well as to develop biomarkers that help in a more accurate and earlier diagnosis. Multiple pieces of evidence including genetic and neuro-imaging studies suggest that mood disorders are associated with abnormalities in endoplasmic-reticulum (ER)-related stress responses, mitochondrial function and calcium signalling. Furthermore, deregulation of the innate immune response has been described in patients diagnosed with mood disorders, including depression and BD. These disease-related events are associated with functions localized to a subdomain of the ER, known as Mitochondria-Associated Membranes (MAMs), which are lipid rafts-like domains that connect mitochondria and ER, both physically and biochemically. This review will outline the current understanding of the role of mitochondria and ER dysfunction under pathological brain conditions particularly in major depressive disorder (MDD) and BD that support the hypothesis that MAMs can act in these mood disorders as the link connecting ER-related stress response and mitochondrial impairment, as well as a mechanisms behind sterile inflammation arising from deregulation of innate immune responses. The role of MAMs in the pathophysiology of these pathologies and its potential relevance as a potential therapeutic target will be discussed.
    Keywords:  Bipolar disorder; ER stress; Inflammation; Major depressive disorder; Mitochondria-associated membranes; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1016/j.bbadis.2020.165752
  6. Biol Chem. 2020 Mar 01. pii: /j/bchm.just-accepted/hsz-2020-0110/hsz-2020-0110.xml. [Epub ahead of print]
    Avendaño-Monsalve MC, Ponce-Rojas JC, Funes S.
      Mitochondrial protein import is one of the key processes during mitochondrial biogenesis that involves a series of events necessary for recognition and delivery of nucleus-encoded/cytosolsynthesized mitochondrial proteins into the organelle. The past research efforts have mainly unraveled how membrane translocases ensure the correct protein sorting within the different mitochondrial subcompartments. However, early steps of recognition and delivery remain relatively uncharacterized. In this review we discuss our current understanding about the signals on mitochondrial proteins as well as in the mRNAs encoding them, that with the help of cytosolic chaperones and membrane receptors, support protein targeting to the organelle in order to avoid improper localization. In addition, we discuss recent findings that illustrate how mistargeting of mitochondrial proteins triggers stress responses, aiming to restore cellular homeostasis.
    Keywords:  heat shock proteins; mRNA targeting; mitochondrial protein import; mitochondrial stress response; ribosomal chaperones; yeast
    DOI:  https://doi.org/10.1515/hsz-2020-0110
  7. Exp Cell Res. 2020 Feb 29. pii: S0014-4827(20)30136-1. [Epub ahead of print] 111931
    Moralli D, Monaco ZL.
      After the construction of genomic libraries with yeast artificial chromosomes in the late 1980's for gene isolation and expression studies in cells, human artificial chromosomes were then a natural development in the 1990's, based on the same principles of formation requiring centromeric sequences for generating functional artificial chromosomes. Over the past twenty years, they became a useful research tool for understanding human chromosome structure and organization, and important vectors for expression of large genes and gene loci and the regulatory regions for full expression. Now they are being modified and developed for gene therapy both ex vivo and in vivo. The advantages of using HAC vectors are that they remain autonomous and behave as a normal chromosome. They are attractive for therapy studies without the harmful consequences of integration of exogenous DNA into host chromosomes. HAC vectors are also the only autonomous stable vectors that accommodate large sequences (>100 kb) compared to other vectors. The challenges of manipulating these vectors for efficient delivery of genes into human cells is still ongoing, but we have made advances in transfer of gene expressing HAC vectors using the helper free (HF) amplicon vector technology for generating de novo HAC in human cells. Efficient multigene delivery was successfully achieved following simultaneous infection with two HF amplicons in a single treatment and the input DNA recombined to form a de novo HAC. Potentially several amplicons containing gene expressing HAC vectors could be transduced simultaneously which would increase the gene loading capacity of the vectors for delivery and studying full expression in human cells.
    Keywords:  Gene therapy; Herpes simplex virus-1 (HSV-1) amplicons; Human artificial chromosome (HAC); Hypoxanthine guanine phosphoribosyltransferase (HPRT) gene; Multigene delivery
    DOI:  https://doi.org/10.1016/j.yexcr.2020.111931