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Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease

1.  Mugdha Joshi1,2,3,10

2.  Irina Anselm4,10

3.  Jiahai Shi5,6

4.  Tejus A. Bale7,

5.  Meghan Towne1,3

6.  Klaus Schmitz-Abe1

7.  Laura Crowley1,3

8.  Felix C. Giani8,9,

9.  Shideh Kazerounian1

10.              Kyriacos Markianos1

11.              Hart G. Lidov7

12.              Rebecca Folkerth7,

13.              Vijay G. Sankaran8,9 and 

14.              Pankaj B. Agrawal1,2,3

+Author Affiliations

1.   1Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
2.   2Division of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
3.   3Gene Discovery Core, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
4.   4Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
5.   5Whitehead Institute for Biomedical Research, MIT, Cambridge, Massachusetts 02142, USA;
6.   6Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China;
7.   7Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA;
8.   8Division of Hematology/Oncology, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts 02115, USA;
9.   9Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

1.   Corresponding author:

1.   10 These authors contributed equally to this work.


We describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCAcDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.



Horizon Pharma plc to Acquire Worldwide Rights to Interferon Gamma-1b From Boehringer Ingelheim International GmbH

20:00 EDT 18 May 2016 | Marketwired

Home » Topics » Top 50 Biopharma Products 2011 » Latest News » Horizon Pharma plc to Acquire Worldwide Rights to Interferon Gamma-1b From Boehringer Ingelheim International GmbH

DUBLIN, IRELAND -- (Marketwired) -- 05/19/16 -- Horizon Pharma plc (NASDAQ: HZNP) ("Horizon Pharma"), a biopharmaceutical company focused on improving patients' lives by identifying, developing, acquiring and commercializing differentiated and accessible medicines that address unmet medical needs, today announced that its affiliate has entered into a definitive agreement with Boehringer Ingelheim International GmbH ("Boehringer Ingelheim") to acquire the rights to interferon gamma-1b, which Boehringer Ingelheim commercializes under the trade names IMUKIN®
and IMMUKINE® in an estimated 30 countries primarily in Europe and the Middle East.

"Obtaining worldwide rights for interferon gamma-1b solidifies our continued investment in the medicine, and pending the outcome of clinical studies investigating it in Friedreich's ataxia and advanced solid tumors, such as kidney and bladder cancer, strengthens our ability to expand its potential global use,"said Timothy P. Walbert, chairman, president and chief executive officer, Horizon Pharma plc.

Under the terms of the agreement, Horizon Pharma paid Boehringer Ingelheim EUR 5 million upon signing and will pay EUR 20 million upon closing for the rights for interferon gamma-1b in all territories outside of the United States, Canada and Japan. Horizon Pharma and Boehringer Ingelheim expect to close the transaction by year-end 2016, subject to the satisfaction of closing conditions.

Under the terms of a separate agreement with an undisclosed third party, Horizon Pharma also licensed the U.S., European and Canadian intellectual property rights for interferon gamma-1b for the treatment of Friedreich's ataxia. Interferon gamma-1b is currently not indicated or approved for the treatment of Friedreich's ataxia.

On May 5, 2016, the Company announced that it completed target enrollment of 90 patients in the Phase 3, randomized, double-blind, placebo controlled STEADFAST study evaluating ACTIMMUNE in patients with Friedreich's ataxia. Top-line results from the trial are expected by the end of 2016.

As a result of the agreement with Boehringer Ingelheim, Horizon Pharma will immediately begin investing in related manufacturing, supply chain, regulatory and commercial activities for interferon gamma-1b. As a result, the Company anticipates a reduction to 2016 adjusted EBITDA of approximately $10 million versus prior guidance.

About Horizon Pharma plc 
Horizon Pharma plc is a biopharmaceutical company focused on improving patients' lives by identifying, developing, acquiring and commercializing differentiated and accessible medicines that address unmet medical needs. Horizon Pharma markets nine medicines through its orphan, rheumatology and primary care business units. Horizon Pharma's global headquarters are in Dublin, Ireland. For more information, please visit Follow @HZNPplc on Twitter or view careers on our LinkedIn page.

Forward-Looking Statements 
This press release contains forward-looking statements, including, but not limited to, statements related to the anticipated consummation of the acquisition of the rights to interferon gamma-1b and the timing and benefits thereof, Horizon Pharma's strategy, plans, objectives, expectations (financial or otherwise) and intentions, the timing of results of the Phase 3 trial of ACTIMMUNE in Friedreich's ataxia, the potential for ACTIMMUNE as a treatment for Friedreich's ataxia and advanced solid tumors, future financial results and growth potential, anticipated product portfolio, development programs and other statements that are not historical facts. These forward-looking statements are based on Horizon's current expectations and inherently involve significant risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in such forward looking statements as a result of these risks and uncertainties, which include, without limitation, risks related to Horizon's ability to complete the transaction on the proposed terms and schedule; risks associated with acquisitions, such as the risk that the businesses will not be integrated successfully, that such integration may be more difficult, time-consuming or costly than expected or that the expected benefits of the transaction will not occur; risks related to future opportunities and plans for the acquired rights and related products; disruption from the proposed transaction, making it more difficult to conduct business as usual or maintain relationships with customers, employees or suppliers; the calculations of, and factors that may impact the calculations of, the acquisition price and the allocation of such acquisition price to the net assets acquired in accordance with applicable accounting rules and methodologies; the possibility that if the acquired rights do not create the perceived benefits of the proposed transaction as rapidly or to the extent anticipated by financial analysts or investors, the market price of the Horizon's shares could decline, risks of delays in completing the Phase 3 trial, risks associated with pre-clinical and clinical development of drug candidates, and risks that the actual effect of additional investments in interferon gamma-1b may differ from its expectations, as well as other risks related to Horizon's business detailed from time-to-time under the caption "Risk Factors" and elsewhere in Horizon Pharma's SEC filings and reports, including in its Annual Report on Form 10-K for the year ended December 31, 2015. Horizon Pharma undertakes no duty or obligation to update any forward-looking statements contained in this presentation as a result of new information, future events or changes in its expectations.

Investors: John Thomas Executive Vice President, Strategy and Investor Relations Tina Ventura Vice President, Investor Relations U.S. Media: Geoff Curtis Senior Vice President, Corporate Communications Ireland Media: Ray Gordon Gordon MRM

Purkinje cell injury, structural plasticity and fusion in patients with Friedreich’s ataxia


·        Amelia J. Cook,

·        Juliana Redondo,

·        Kathreena M. Kurian,

·        Neil J. Scolding and

·        Alastair Wilkins


Purkinje cell pathology is a common finding in a range of inherited and acquired cerebellar disorders, with the degree of Purkinje cell injury dependent on the underlying aetiology. Purkinje cells have an unparalleled resistance to insult and display unique regenerative capabilities within the central nervous system. Their response to cell injury is not typical of most neurons and likely represents both degenerative, compensatory and regenerative mechanisms. Here we present a pathological study showing novel and fundamental insights into Purkinje cell injury, remodelling and repair in Friedreich’s ataxia; the most common inherited ataxia. Analysing post-mortem cerebellum tissue from patients who had Friedreich's ataxia, we provide evidence of significant injury to the Purkinje cell axonal compartment with relative preservation of both the perikaryon and its extensive dendritic arborisation. Axonal remodelling of Purkinje cells was clearly elevated in the disease. For the first time in a genetic condition, we have also shown a disease-related increase in the frequency of Purkinje cell fusion and heterokaryon formation in Friedreich's ataxia cases; with evidence that underlying levels of cerebellar inflammation influence heterokaryon formation. Our results together further demonstrate the Purkinje cell’s unique plasticity and regenerative potential. Elucidating the biological mechanisms behind these phenomena could have significant clinical implications for manipulating neuronal repair in response to neurological injury.



Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

·        Mohammed Akbara, , 1

·        Musthafa Mohamed Essab, c, , 1

·        Ghazi Daradkehb, 1

·        Mohamed A. Abdelmegeeda

·        Youngshim Choia

·        Lubna Mahmoodd

·        Byoung-Joon Songa, 


Mitochondria are important for providing cellular energy ATP through the oxidative phosphorylation pathway. They are also critical in regulating many cellular functions including the fatty acid oxidation, the metabolism of glutamate and urea, the anti-oxidant defense, and the apoptosis pathway. Mitochondria are an important source of reactive oxygen species leaked from the electron transport chain while they are susceptible to oxidative damage, leading to mitochondrial dysfunction and tissue injury. In fact, impaired mitochondrial function is commonly observed in many types of neurodegenerative diseases, including Alzheimer’s disease, Parkinson׳s disease, Huntington׳s disease, alcoholic dementia, brain ischemia-reperfusion related injury, and others, although many of these neurological disorders have unique etiological factors. Mitochondrial dysfunction under many pathological conditions is likely to be promoted by increased nitroxidative stress, which can stimulate post-translational modifications (PTMs) of mitochondrial proteins and/or oxidative damage to mitochondrial DNA and lipids. Furthermore, recent studies have demonstrated that various antioxidants, including naturally occurring flavonoids and polyphenols as well as synthetic compounds, can block the formation of reactive oxygen and/or nitrogen species, and thus ultimately prevent the PTMs of many proteins with improved disease conditions. Therefore, the present review is aimed to describe the recent research developments in the molecular mechanisms for mitochondrial dysfunction and tissue injury in neurodegenerative diseases and discuss translational research opportunities.



Frataxin and the molecular mechanism of mitochondrial iron-loading in Friedreich's ataxia


Shannon Chiang, Zaklina Kovacevic, Sumit Sahni, Darius J.R. 

Lane, Angelica M. Merlot,Danuta S. Kalinowski, Michael L.-H. Huang, Des R. Richardson


The mitochondrion is a major site for the metabolism of the transition metal, iron, which is necessary for metabolic processes critical for cell vitality. The enigmatic mitochondrial protein, frataxin, is known to play a significant role in both cellular and mitochondrial iron metabolism due to its iron-binding properties and its involvement in iron–sulfur cluster (ISC) and heme synthesis. The inherited neuro- and cardio-degenerative disease, Friedreich's ataxia (FA), is caused by the deficient expression of frataxin that leads to deleterious alterations in iron metabolism. These changes lead to the accumulation of inorganic iron aggregates in the mitochondrial matrix that are presumed to play a key role in the oxidative damage and subsequent degenerative features of this disease. Furthermore, the concurrent dys-regulation of cellular antioxidant defense, which coincides with frataxin deficiency, exacerbates oxidative stress. Hence, the pathogenesis of FA underscores the importance of the integrated homeostasis of cellular iron metabolism and the cytoplasmic and mitochondrial redox environments. This review focuses on describing the pathogenesis of the disease, the molecular mechanisms involved in mitochondrial iron-loading and the dys-regulation of cellular antioxidant defense due to frataxin deficiency. In turn, current and emerging therapeutic strategies are also discussed.


University of Alabama utilizes Mawi’s iSWAB-Protein buccal cell collection device for the detection of the mitochondrial protein Frataxin

Dr. Jill Butler from Dr. Marek Napierala’s lab at the University of Alabama Stem Cell Institute used our iSWAB-Protein non-invasive sample collection system for biomarker detection in buccal cells.

Based on her data Dr. Butler had this to say about iSWAB-Protein:
“We were pleasantly surprised with the quality of the western blot data given the ease of collection and sample processing.”
Detection of Frataxin using iSWAB-Protein UAB

Dr. Butler is now expanding her studies to other biomarkers of interest and will be sharing additional data with us soon!



Dual Role of ROS as Signal and Stress Agents: Iron Tips the Balance in favor of Toxic Effects

Elena GammellaStefania Recalcati, and Gaetano Cairo

Department of Biomedical Sciences for Health, University of Milan, 20133 Milan, Italy


Iron is essential for life, while also being potentially harmful. Therefore, its level is strictly monitored and complex pathways have evolved to keep iron safely bound to transport or storage proteins, thereby maintaining homeostasis at the cellular and systemic levels. These sequestration mechanisms ensure that mildly reactive oxygen species like anion superoxide and hydrogen peroxide, which are continuously generated in cells living under aerobic conditions, keep their physiologic role in cell signaling while escaping iron-catalyzed transformation in the highly toxic hydroxyl radical. In this review, we describe the multifaceted systems regulating cellular and body iron homeostasis and discuss how altered iron balance may lead to oxidative damage in some pathophysiological settings.



Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia

Dörte Poburski, Josefine Barbara Boerner, Michel Koenig, Michael Ristow, René Thierbach


Friedreich ataxia is a neurodegenerative disease caused by a GAA triplet repeat expansion in the first intron of the frataxin gene, which results in reduced expression levels of the corresponding protein. Despite numerous animal and cellular models, therapeutic options that mechanistically address impaired frataxin expression are lacking. Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxinknockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. After loss of frataxin protein, cell division, aconitase activity and oxygen consumption rates were found to be decreased, while ROS production was increased in the homozygous state. By contrast, in the heterozygous state no such changes were observed. A time-resolved analysis revealed the loss of aconitase activity as an initial event after induction of complete frataxin deficiency, followed by secondarily elevated ROS production and a late increase in iron content. Initial impairments of oxygen consumption and ATP production were found to be compensated in the late state and seemed to play a minor role in Friedreich ataxia pathophysiology. In conclusion and as predicted from its proposed role in iron sulfur cluster (ISC) biosynthesis, disruption of frataxin primarily causes impaired function of ISC-containing enzymes, whereas other consequences, including elevated ROS production and iron accumulation, appear secondary. These parameters and the robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner.



Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Noemí Esteras1 / Albena T. Dinkova-Kostova23 / Andrey Y. Abramov1

1UCL Institute of Neurology, Department of Molecular Neuroscience, London WC1N 3BG, UK

2Jacqui Wood Cancer, Division of Cancer Research, School of Medicine, University of Dundee, Dundee DD1 9SY, Scotland, UK

3Departments of Medicine and Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA

We thank all members of our laboratories who have contributed to these studies. N.E. holds a postdoctoral fellowship from Fundación Alfonso Martín Escudero, Spain. We are grateful to Cancer Research UK (C20953/A18644), and the Biotechnology and Biological Sciences Research Council (BB/L01923X/1) for financial support. The work was undertaken at University College London (UCL), which receives support from the Department of Health’s NIHR Biomedical Research Centre’s funding streams.


The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor well-known for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.


Cardiac Serum Biomarkers in Friedreich Ataxia May Reflect Fibrosis, Myocyte Injury, and Degree of Hypertrophy

C. Bui


 R.B. Wilson


 D.R. Lynch


 J.W. Rossano


 O. Elci


 K.Y. Lin

Friedreich Ataxia (FA) is a hereditary ataxia disorder with an associated hypertrophic cardiomyopathy, caused by a deficiency in the mitochondrial protein frataxin. Heart disease is the most common cause of premature death in FA, but little is known about the utility of various biomarkers in FA-related cardiomyopathy. We hypothesized that serum markers of cardiac injury, stress, fibrosis, and inflammation are higher in FA subjects than non-FA controls, and these markers correlate with echocardiographic markers of cardiomyopathy.


Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients With Friedreich Ataxia

Pamela C. Kruger, PhD


 Karl X. Yang, PhD


 Patrick J. Parsons, PhD


 Alyssa B. Becker, BA


 Paul J. Feustel, PhD


 Arnulf H. Koeppen, MD

Cardiomyopathy is a frequent cause of death in patients with Friedreich ataxia (FA), and a characteristic pathological feature is the focal accumulation of iron (Fe) in cardiomyocytes. This restricted localization of the metal contrasts with the diffuse cardiac Fe overload in hemochromatosis and transfusion siderosis. Nevertheless, heart Fe in FA contributes to cardiomyocyte necrosis, inflammation, and scarring as the disease progresses. A putative mechanism of cardiomyopathy in FA is Fe-mediated oxidative damage. Two other transition metals zinc (Zn) and copper (Cu), are diffusely distributed throughout normal hearts and the hearts of patients with FA. The myocardium in FA is also prone to deposits of calcium in the form of scattered concretions. In this study, heart tissues (left and right ventricular walls and ventricular septum) of 23 patients with genetically confirmed FA and 8 normal controls were obtained at autopsy and analyzed for Fe, Zn, Cu, and calcium. The principal assay methods were inductively coupled plasma optical emission spectrometry and plasma mass spectrometry. Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA. In conclusion, the decrease of Cu may be important in consideration of the potential benefit of Cu supplements in FA cardiomyopathy.



Idebenone in Friedreich ataxia and Leber’s hereditary optic neuropathy: close mechanisms, similar therapy?


Manuel Schiff, Pierre Rustin

DOI: aww085 First published online: 19 April 2016


In 1999, we reported in a preliminary study that idebenone (Mnesis) decreased heart hypertrophy in three young patients with Friedreich ataxia, possibly with slight improvement in delicate movements (Rustin et al., 1999b). In the vast majority of patients with Friedreich ataxia, an abnormal GAA expansion is found in the first intron of the frataxin (FXN) gene impairing transcription of the gene (Campuzano et al., 1996). The resulting loss of function of the mitochondria-targeted frataxin protein leads to a deficiency of the mitochondrial iron-sulphur containing proteins (ISP), including complexes I, II and III of the respiratory chain in the heart of the patients (Rotig et al., 1997). Defect of the ISP was shown to cause an iron-dependent oxidative stress which could be controlled in vitro by reduced idebenone (Rustin et al., 1999a). In vivo, idebenone can be reduced by respiratory chain and/or NQO1 (NADH quinone oxidoreductase) activity (Haefeli et al., 2011). Following the preliminary report of idebenone efficacy to counteract …



Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia

Subrahamanyam Dantham


 Achal K. Srivastava


 Sheffali Gulati


 Moganty R. Rajeswari


Friedreich's ataxia (FRDA) is one of the most devastating childhood onset neurodegenerative disease affecting multiple organs in the course of progression. FRDA is associated with mitochondrial dysfunction due to deficit in a nuclear encoded mitochondrial protein, frataxin. Identification of disease-specific biomarker for monitoring the severity remains to be a challenging topic. This study was aimed to identify whether circulating cell-free nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) in blood plasma can be a potential biomarker for FRDA. Clinical information was assessed using International Cooperative Ataxia Rating Scale and the disease was confirmed using Long-range PCR for GAA repeat expansion within the gene encoding frataxin. The frataxin expression was measured using Western blot. Plasma nDNA and mtDNA levels were quantified by Multiplex real-time PCR. The major observation is that the levels of nDNA found to be increased, whereas mtDNA levels were reduced significantly in the plasma of FRDA patients (n = 21) as compared to healthy controls (n = 21). Further, plasma mtDNA levels showed high sensitivity (90%) and specificity (76%) in distinguishing from healthy controls with optimal cutoff indicated at 4.1 × 105 GE/mL. Interestingly, a small group of follow-up patients (n = 9) on intervention with, a nutrient supplement, omega-3 fatty acid (a known enhancer of mitochondrial metabolism) displayed a significant improvement in the levels of plasma mtDNA, supporting our hypothesis that plasma mtDNA can be a potential monitoring or prognosis biomarker for FRDA.

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ataxia

Belén Mollá, Fátima Riveiro, Arantxa Bolinches-Amorós, Diana C. Muñoz-Lasso, Francesc Palau, Pilar González-Cabo


Frataxin deficiency causes Friedreich ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, patients are affected by non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in posterior columns and brain, which agree with the existence of a dying back process similar to described in FRDA patients. In YG8R we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cell may underlay the nerve pathology. In pancreas we found high proportion of senescent islets of Langerhans in YG8R mice that makes the β cell number and islet mass decrease to pathological levels, since they are unable to maintain normoglycemia. As a whole, these results confirm that the lack of frataxin induces different pathogenic mechanisms in nervous system and pancreas in the mouse model of FRDA: sensory nerve dying-back and pancreatic senescence.




Development of an AAV9 coding for a 3XFLAG-TALEfrat#8-VP64 able to increase in vivo the human frataxin in YG8R mice

P Chapdelaine1,2, C Gérard1,2, N Sanchez1,2, K Cherif1,2, J Rousseau1,2, D L Ouellet1,2, D Jauvin1,2 and J P Tremblay1,2

1.   1Unité de Génétique Humaine, Axe Neurosciences, Centre de Recherche du Centre Hospitalier de Universitaire de Québec-Université Laval, Québec City, QC, Canada

2.   2Department of Molecular Medicine, Faculty of Medicine, Laval University, Quebec City, QC, Canada

Correspondence: Professor JP Tremblay, Unité de Génétique humaine, Axe Neurosciences, Centre de Recherche du Centre Hospitalier Universitaire de Universitaire de Québec-Université Laval, CRCHUL 2705 Boulevard Laurier, Room P09300, Québec City, QC, Canada G1V4G2. E-mail:


Artificially designed transcription activator-like effector (TALE) proteins fused to a transcription activation domain (TAD), such as VP64, are able to activate specific eukaryotic promoters. They thus provide a good tool for targeted gene regulation as a therapy. However, the efficacy of such an agent in vivo remains to be demonstrated as the majority of studies have been carried out in cell culture. We produced an adeno-associated virus 9 (AAV9) coding for a TALEfrat#8 containing 13 repeat variable diresidues able to bind to the proximal promoter of human frataxin (FXN) gene. This TALEfrat#8 was fused with a 3XFLAG at its N terminal and a VP64 TAD at its C terminal, and driven by a CAG promoter. This AAV9_3XFLAG-TALEfrat#8-VP64 was injected intraperitoneally to 9-day-old and 4-month-old YG8R mice. After 1 month, the heart, muscle and liver were removed and their FXN mRNA and FXN protein were analyzed. The results show that the AAV9_3XFLAG-TALEfrat#8-VP64 increased the FXN mRNA and FXN protein in the three organs studied. These results corroborate our previous in vitrostudies in the FRDA human fibroblasts. Our study indicates that an AAV coding for a TALE protein coupled with a TAD may be used to increase gene expression in vivo as a possible treatment not only for FRDA but also for other haploinsufficiency diseases.



Lymphoblast Oxidative Stress Genes as Potential Biomarkers of Disease Severity and Drug Effect in Friedreich's Ataxia

·        Genki Hayashi,

·        Gino Cortopassi 


There is no current approved therapy for the ultimately lethal neuro- and cardio-degenerative disease Friedreich's ataxia (FA). Finding minimally-invasive molecular biomarkers of disease progression and drug effect could support smaller, shorter clinical trials. Since we and others have noted a deficient oxidative stress response in FA, we investigated the expression of 84 genes involved in oxidative stress, signaling, and protection in control and FA lymphoblasts ranging from 460 to 1122 GAA repeats. Several antioxidant genes responded in a dose-dependent manner to frataxin expression at the mRNA and protein levels, which is inversely correlated with disease progression and severity. We tested the effect of experimental Friedreich’s ataxia therapies dimethyl fumarate (DMF) and type 1 histone deacetylase inhibitor (HDACi) on biomarker mRNA expression. We observed that exposure of lymphoblasts to DMF and HDACi dose-dependently unsilenced frataxin expression and restored the potential biomarkers NCF2 and PDLIM1 expression to control levels. We suggest that in addition to frataxin expression, blood lymphoblast levels of NCF2 and PDLIM1 could be useful biomarkers for disease progression and drug effect in future clinical trials of Friedreich’s ataxia.




Comorbid Medical Conditions in Friedreich Ataxia

Association With Inflammatory Bowel Disease and Growth Hormone Deficiency

1.  Julianna E. Shinnick, BA1

2.  Kimberly Schadt, MSN1

3.  Cassandra Strawser, BA1

4.  Nicholas Wilcox, BS1

5.  Susan L. Perlman, MD3

6.  George R. Wilmot, MD, PhD4

7.  Christopher M. Gomez, MD, PhD5

8.  Katherine D. Mathews, MD6

9.  Grace Yoon, MD7

10.              Theresa Zesiewicz, MD8

11.              Chad Hoyle, MD9

12.              S. H. Subramony, MD10

13.              Eppie M. Yiu, MD11

14.              Martin B. Delatycki, MD11

15.              Alicia F. Brocht, MS12

16.              Jennifer M. Farmer, MS1

17.              David R. Lynch, MD, PhD1,2

1.   1Departments of Pediatrics and Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
2.   2Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
3.   3Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA
4.   4Department of Neurology, Emory University, Atlanta, GA, USA
5.   5Department of Neurology, University of Chicago, Chicago, IL, USA
6.   6Department of Neurology, University of Iowa, Iowa City, IA, USA
7.   7Division of Clinical and Metabolic Genetics, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
8.   8Department of Neurology, University of South Florida, and the James A. Haley Veterans’ Administration Hospital, Tampa, FL, USA
9.   9Department of Neurology, Ohio State University, Columbus, OH, USA
10.       10Department of Neurology, University of Florida, Gainesville, FL, USA
11.       11Murdoch Children’s Research Institute, Melbourne, Australia
12.       12Department of Neurology, University of Rochester, Rochester, NY, USA

1.   David R. Lynch, MD, PhD, Division of Neurology, Children’s Hospital of Philadelphia, 502 Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA 19104, USA. Email:


Friedreich ataxia is a progressive degenerative disease with neurologic and cardiac involvement. This study characterizes comorbid medical conditions in a large cohort of patients with Friedreich ataxia. Patient diagnoses were collected in a large natural history study of 641 subjects. Prevalence of diagnoses in the cohort with Friedreich ataxia was compared with prevalence in the population without Friedreich ataxia. Ten patients (1.6%) had inflammatory bowel disease, 3.5 times more common in this cohort of individuals with Friedreich ataxia than in the general population. Four subjects were growth hormone deficient, reflecting a prevalence in Friedreich ataxia that is 28 times greater than the general population. The present study identifies specific diagnoses not traditionally associated with Friedreich ataxia that are found at higher frequency in this disease. These associations could represent coincidence, shared genetic background, or potentially interactive disease mechanisms with Friedreich ataxia.



Researchers from Mount Sinai and Sage Bionetworks Report Analysis of Nearly 600,000 Genomes for Resilience Project


 – April 11, 2016 /Press Release/  –– 

As part of a global collaboration, scientists from the Icahn School of Medicine at Mount Sinai and Sage Bionetworks conducted the largest genome study to date and reported the first systematic search across hundreds of Mendelian disorders in hundreds of thousands of individuals apparently not afflicted with any of these disorders to identify those carrying disease protective factors. This retrospective study of more than 589,000 genomes was a first step for the Resilience Project and was performed with researchers from 23andMe, BGI, the Ontario Institute for Cancer Research, and other institutions.

The Resilience Project launched in 2014 with a unique vision by Stephen Friend and Eric Schadt that by studying massive numbers of healthy adults, scientists might find rare individuals who are unaffected by genetic variants that should induce disease. Genome analysis of these resilient people could uncover naturally occurring, protective mechanisms that would serve as novel treatments for people affected by these diseases.

“Most genomic studies focus on finding the cause of a disease, but we see tremendous opportunity in figuring out what keeps people healthy,” said Eric Schadt, PhD, the Jean C. and James W. Crystal Professor of Genomics at the Icahn School of Medicine at Mount Sinai, and Founding Director of the Icahn Institute for Genomics and Multiscale Biology. “Millions of years of evolution have produced far more protective mechanisms than we currently understand. Characterizing the intricacies of our genomes will ultimately reveal elements that could promote health in ways we haven’t even imagined.”

In this study, researchers analyzed DNA from 12 previously collected data sets, using a newly developed targeted sequencing panel to screen 874 genes for 584 distinct genetic diseases. The diseases, which were mostly metabolic conditions, neurological diseases, or developmental disorders, present in childhood with severe symptoms. All genomes analyzed were from adults who had never been diagnosed with any of these diseases. A sophisticated, in-depth analysis process identified 13 healthy people with genetic variants associated with eight diseases.

“This study demonstrates the power of using big data to ask new biological questions,” said Anne Wojcicki, co-founder and CEO of 23andMe, which participated in the project. “More than 400,000 23andMe customers contributed to this effort, showing that engaged consumers can make a real impact on scientific research.”

In narrowing the pool of potentially resilient people from an original list of nearly 16,000 candidates, the researchers encountered two significant challenges. First, more than 75% of the candidates were eliminated due to inaccurate or low-confidence variant calls in the existing data, highlighting the need for better protocols and standards for interpreting genetic data. Second, none of the 13 final candidates could be contacted with follow-up questions due to limitations in the original studies’ informed consent policies. It will be impossible to determine whether these people are truly resistant to disease without additional information.

“There’s an important lesson here for genome scientists around the world: the value of any project becomes exponentially greater when informed consent policies allow other scientists to reach out to the original study participants,” said Stephen Friend, President of Sage Bionetworks, Professor of Genomics at the Icahn School of Medicine, and co-founder of the Resilience Project. “If we could contact these 13 people, we might be even closer to finding natural protections against disease. We anticipate launching a prospective study in the future that will include a more broadly useful consent policy.”

"While most genomics research in medicine has been disease focused, this important work exemplifies the benefit of studying health and resilience—the converse of disease—to understand the mechanism for protection in individuals with pathogenic sequence variants,” said Eric Topol, MD, Director of the Scripps Translational Science Institute, and Chief Academic Officer of Scripps Health, who was not involved in this study but has been a champion of shifting the research focus to include healthy individuals. “This makes for a standout contribution from the Icahn Institute, Sage Bionetworks, and their extensive network of collaborators.”

“This work demonstrates the power of scale in analyzing root genetic causes of human disease, but more importantly human health. Its focus on studying healthy individuals to understand the things that keep them healthy sounds obvious but actually lies at the vanguard of a movement which puts the engaged study participant at the center of scientific research,” said Vik Bajaj, PhD, Chief Scientific Officer of Verily, who was not involved in this study but has advocated for harnessing big data for improved healthcare. “This research also points to the need for more effective standardization in the generation and analysis of genetic data, a field in which the authors are pre-eminent practitioners.”

Paper cited:
Rong Chen, Lisong Shi, et al. Analysis of 589,306 genomes identifies individuals resilient to severe Mendelian childhood diseases. Nature Biotechnology. DOI:10.1038/NBT.3514

For more information about the Resilience Project, visit





Italian program for independent research on drugs: 10 year follow-up of funded studies in the area of rare diseases

·        Giuseppe Traversa

·        Luciano Sagliocca and

·        Francesco Trotta



In 2005 the Italian Medicines Agency (AIFA) started a program on independent research on drugs, with the aim to promote clinical research in areas of limited commercial interest. For 3 years (2005–2007) an area of the program was reserved to studies in the field of rare diseases. There is a concern that public funding of research may be wasted. We investigated the outcome of the program.


We conducted a cohort study on the projects that were funded by the AIFA in the area of rare diseases. The outcomes were the proportion of published studies, time to publication, impact factor of the publishing journals and relevance for clinical practice. We retrieved published articles through a literature search in peer reviewed biomedical journals indexed by Pubmed. We used the Kaplan–Meier method to estimate the cumulative probability of publication by time from project starting to publication.


During the period 2005–2007, 62 projects were funded in the area of rare diseases. Most of the studies (n 39; 63 %) had a randomized design and in 22 (35 %) the control group received an active treatment. For 39 studies (63 %) we retrieved a publication in a peer reviewed journal. The median time to publication was 74 months and, at the maximum period of follow up (109 months), the cumulative probability of publication reached 77 %. The median impact factor was 5.4 (range 1.4–52.4). Considering the clinical relevance, more than 30 % of the published articles presented conclusive findings; an additional 10 % of the studies reached potential breakthrough findings.


Even though it takes time to set up and conduct a funding program for independent research on drugs, the results are highly rewarding. Independent funding is crucial in supporting studies aimed at answering questions that are relevant for clinical practice despite the lack of sufficient commercial interest.


Independent research Rare diseases Clinical trials Cohort studies Bibliometrics



Statistical Enrichment of Epigenetic States Around Triplet Repeats that Can Undergo Expansions Essebier1, Vera Wolf1, Duc Cao1, J. Carroll1, Balasubramanian2* and Bodén1*

·        1School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia

·        2School of Biological Sciences, Monash University, Melbourne, VIC, Australia

More than 30 human genetic diseases are linked to tri-nucleotide repeat expansions. There is no known mechanism that explains repeat expansions in full, but changes in the epigenetic state of the associated locus has been implicated in the disease pathology for a growing number of examples. A comprehensive comparative analysis of the genomic features associated with diverse repeat expansions has been lacking. Here, in an effort to decipher the propensity of repeats to undergo expansion and result in a disease state, we determine the genomic coordinates of tri-nucleotide repeat tracts at base pair resolution and computationally establish epigenetic profiles around them. Using three complementary statistical tests, we reveal that several epigenetic states are enriched around repeats that are associated with disease, even in cells that do not harbor expansion, relative to a carefully stratified background. Analysis of over one hundred cell types reveals that epigenetic states generally tend to vary widely between genic regions and cell types. However, there is qualified consistency in the epigenetic signatures of repeats associated with disease suggesting that changes to the chromatin and the DNA around an expanding repeat locus are likely to be similar. These epigenetic signatures may be exploited further to develop models that could explain the propensity of repeats to undergo expansions.




Roles of Fe–S proteins: from cofactor synthesis to iron homeostasis to protein synthesis

·        Debkumar Pain1

·        Andrew Dancis2, 

Fe–S cluster assembly is an essential process for all cells. Impairment of Fe–S cluster assembly creates diseases in diverse and surprising ways. In one scenario, the loss of function of lipoic acid synthase, an enzyme with Fe–S cluster cofactor in mitochondria, impairs activity of various lipoamide-dependent enzymes with drastic consequences for metabolism. In a second scenario, the heme biosynthetic pathway in red cell precursors is specifically targeted, and iron homeostasis is perturbed, but lipoic acid synthesis is unaffected. In a third scenario, tRNA modifications arising from action of the cysteine desulfurase and/or Fe–S cluster proteins are lost, which may lead to impaired protein synthesis. These defects can then result in cancer, neurologic dysfunction or type 2 diabetes.



Effects of Genetic Severity on Glucose Homeostasis in Friedreich Ataxia

1.   Charles J. Isaacs BA1, 

2.   Karlla W. Brigatti MS1, 

3.   Olena Kucheruk RN MPH2, 

4.   Sarah Ratcliffe PhD2, 

5.   Tom Sciascia MD3, 

6.   Shana E. McCormack MD2, 

7.   Steven M. Willi MD2,†and

8.   David R. Lynch MD PhD1,* Abstract

Introduction: Friedreich ataxia (FRDA) leads to increased risk of diabetes. Less is known regarding the dynamics of glucose homeostasis in FRDA, the influence of disease features, and the utility of oral-based metrics for capturing metabolic dysfunction.

Methods: To examine these dynamics, we analyzed oral and intravenous glucose tolerance test data in 42 non-diabetic patients with FRDA.

Results: Patients showed high insulin responsiveness to glucose and low insulin sensitivity. Genetic severity predicted overall metabolic impairment: individuals with longer guanineadenine-adenine (GAA) repeats on the shorter allele showed a lower disposition index. Genetic severity did not predict any other variables. Measures of disposition index from intravenous and oral glucose tolerance testing did not correlate well, possibly reflecting divergent responses to oral and IV glucose loads.

Discussion: FRDA patients demonstrate abnormal compensatory activity for managing glucose. Genetic severity impacts the global homeostatic profile, whereas relative contributions of insulin secretion and action vary from patient-to-patient. This article is protected by copyright. All rights reserved.




Mouvements oculaires anormaux : aide au diagnostic étiologique/topographique en neurologie

Abnormal eye movements: Etiologic/topographic diagnostic tool in neurology

·        C. Tiliketea, , b, 


Les nystagmus acquis centraux ou les autres types de mouvements oculaires anormaux d’origine neurologique ont pour certains une valeur séméiologique intéressante. Le mouvement oculaire anormal doit être identifié par une observation précise du type de phase (lente ou rapide), de la direction, de son caractère mono- ou binoculaire, de sa fréquence et de sa régularité, et dans le contexte pathologique général. Lorsque l’identification est précise et correcte, il peut être un outil essentiel pour établir un diagnostic topographique, étiologique et/ou pronostique de certaines affections neurologiques. Nous proposons dans ce chapitre une approche « pratique » visant à sensibiliser le neurologue à l’observation de mouvements oculaires anormaux pour améliorer la finesse du diagnostic clinique.


Acquired neurological nystagmus and other abnormal eye movements may be valuable diagnostic tools. The identification of abnormal eye movement is based on close observation of the slow or quick phase, direction, monocular or binocular characteristic, frequency, regularity and of the general pathological context. In case of precise and correct identification, it can be a challenging tool to establish a topology, etiology or prognosis of some neurological diseases. Here, we provide a “practical” approach, with the objective of highlighting for neurologists the importance of abnormal eye movement observation in order to improve the subtlety of clinical diagnosis.





New tool enables scientists to interpret 'dark matter' DNA

Breakthrough technology opens the door to identifying new drug targets that could treat many genetic diseases


April 4, 2016


Gladstone Institutes


Scientists have invented a new way to read and interpret the human genome. The computational method, called TargetFinder, can predict where non-coding DNA -- the DNA that does not code for proteins -- interacts with genes. This technology helps researchers connect mutations in the so-called genomic 'dark matter' with the genes they affect, potentially revealing new therapeutic targets for genetic disorders.


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Scientists at the Gladstone Institutes have invented a new way to read and interpret the human genome. The computational method, called TargetFinder, can predict where non-coding DNA--the DNA that does not code for proteins--interacts with genes. This technology helps researchers connect mutations in the so-called genomic "dark matter" with the genes they affect, potentially revealing new therapeutic targets for genetic disorders.





Role of neuroimaging in the diagnosis of hereditary cerebellar ataxias in childhood

·        Giulia Peruccaa, , , 

·        Nicolas Leboucqb, , 

·        Agathe Roubertiec, , 

·        François Rivierc, , 

·        Nicolas Menjotb, , 

·        Consuelo Valentinid, , 

·        Alain Bonafeb,  Summary

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, characterized by cerebellar ataxia as the main clinical feature, and a large spectrum of neurological-associated symptoms and possible multi-organ affection. Image-based approaches to hereditary ataxias in childhood have already been proposed. The aim of this review is to yield the main reports of neuroimaging patterns and diagnostic algorithms and compare them with the results from our study of 23 young patients addressed for ataxia, with subsequent genetic or metabolic diagnosis.


·        A-T, ataxia-telangiectasia; 

·        AD, Alexander disease; 

·        CDG-Ia, congenital disorder of glycosylation type Ia; 

·        CMD1A, congenital muscular dystrophy type 1A; 

·        CS, Cockayne syndrome; 

·        FRDA, Friedreich ataxia; 

·        H-ABC, hypomyelination with atrophy of the basal ganglia and cerebellum; 

·        l-2-HGA, l-2-hydroxyglutaric aciduria; 

·        MSS, Marinesco–Sjögren syndrome; 

·        MLD, metachromatic leukodystrophy; 

·        MMA/HC cbIC,methylmalonic acidemia with homocystinuria cbIC; 

·        MNGIE, mitochondrial neurogastrointestinal encephalopathy syndrome; 

·        NCL, neuronal ceroid lipofuscinoses;

·        PDHD, pyruvate dehydrogenase complex deficiency




Neurodegenerative diseases and therapeutic strategies using iron chelators

·        Roberta J. Warda, b, , , 

·        David T. Dextera

·        Robert R. Crichtonb



This review will summarise the current state of our knowledge concerning the involvement of iron in various neurological diseases and the potential of therapy with iron chelators to retard the progression of the disease. We first discuss briefly the role of metal ions in brain function before outlining the way by which transition metal ions, such as iron and copper, can initiate neurodegeneration through the generation of reactive oxygen and nitrogen species. This results in protein misfolding, amyloid production and formation of insoluble protein aggregates which are contained within inclusion bodies. This will activate microglia leading to neuroinflammation. Neuroinflammation plays an important role in the progression of the neurodegenerative diseases, with activated microglia releasing pro-inflammatory cytokines leading to cellular cell loss. The evidence for metal involvement in Parkinson's and Alzheimer's disease as well as Friedreich's ataxia and multiple sclerosis will be presented. Preliminary results from trials of iron chelation therapy in these neurodegenerative diseases will be reviewed.



Intracellular Delivery of Proteins with Cell-Penetrating Peptides for Therapeutic Uses in Human Disease

Ana Dinca 1, Wei-Ming Chien 2 and Michael T. Chin 1,2,*


Department of Pathology, University of Washington, Seattle, WA 98109, USA


Department of Medicine, Division of Cardiology, University of Washington, Seattle, WA 98109, USA


Correspondence: Tel.: +1-206-616-8880

Academic Editor: Jagdish Singh

Received: 7 January 2016 / Accepted: 16 February 2016 / Published: 22 February 2016


: Protein therapy exhibits several advantages over small molecule drugs and is increasingly being developed for the treatment of disorders ranging from single enzyme deficiencies to cancer. Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered proteins. Although the molecular mechanisms of uptake are not firmly established, CPPs have been empirically shown to promote uptake of various molecules, including large proteins over 100 kiloDaltons (kDa). Recombinant proteins that include a CPP tag to promote intracellular delivery show promise as therapeutic agents with encouraging success rates in both animal and human trials. This review highlights recent advances in protein-CPP therapy and discusses optimization strategies and potential detrimental effects.



Genome-editing Technologies for Gene and Cell Therapy

Morgan L Maeder1 and Charles A Gersbach2,3,4

1.   1Editas Medicine, Cambridge, Massachusetts, USA

2.   2Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA

3.   3Center for Genomic and Computational Biology, Duke University, Durham, North Carolina, USA

4.   4Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina, USA

Correspondence: Morgan L Maeder, Editas Medicine, 300 Third Street, First Floor, Cambridge, Massachusetts 02142, USA. E-mail:; Charles A Gersbach, Department of Biomedical Engineering, Room 1427, FCIEMAS, 101 Science Drive, Box 90281, Duke University, Durham, North Carolina 27708-0281, USA. E-mail:


Gene therapy has historically been defined as the addition of new genes to human cells. However, the recent advent of genome-editing technologies has enabled a new paradigm in which the sequence of the human genome can be precisely manipulated to achieve a therapeutic effect. This includes the correction of mutations that cause disease, the addition of therapeutic genes to specific sites in the genome, and the removal of deleterious genes or genome sequences. This review presents the mechanisms of different genome-editing strategies and describes each of the common nuclease-based platforms, including zinc finger nucleases, transcription activator-like effector nucleases (TALENs), meganucleases, and the CRISPR/Cas9 system. We then summarize the progress made in applying genome editing to various areas of gene and cell therapy, including antiviral strategies, immunotherapies, and the treatment of monogenic hereditary disorders. The current challenges and future prospects for genome editing as a transformative technology for gene and cell therapy are also discussed.

The realization of the genetic basis of hereditary disease led to the early concept of gene therapy in which “exogenous ‘good’ DNA be used to replace the defective DNA in those who suffer from genetic defects”.1 More than 40 years of research since this proposal of gene therapy has shown the simple idea of gene replacement to be much more challenging and technically complex to implement both safely and effectively than originally appreciated. Many of these challenges centered on fundamental limitations in the ability to precisely control how genetic material was introduced to cells. Nevertheless, the technologies for addition of exogenous genes have made remarkable progress during this time and are now showing promising clinical results across a range of strategies and medical indications.2 However, several challenges still remain. Integrating therapeutic genes into the genome for stable maintenance in replicating cells can have unpredictable effects on gene expression and unintended effects on neighboring genes.3 Moreover, some therapeutic genes are too large to be readily transferred by available delivery vectors. Finally, the addition of exogenous genes cannot always directly address dominant mutations or remove unwanted genetic material such as viral genomes or receptors. To address these fundamental limitations of conventional methods for gene addition, the field of gene editing has emerged to make precise, targeted modifications to genome sequences. Here we review the recent exciting developments in the ease of use, specificity, and delivery of gene-editing technologies and their application to treating a wide variety of diseases and disorders.



New developments and controversies in iron metabolism and iron chelation therapy

Christina N Kontoghiorghe, George J Kontoghiorghes

Christina N Kontoghiorghe, George J Kontoghiorghes, Postgraduate Research Institute of Science, Technology, Environment and Medicine, Limassol 3021, Cyprus

Author contributions: Kontoghiorghe CN contributed to the literature background on recent developments on iron metabolism and chelation and critically reviewed the clinical and other aspects of the manuscript; Kontoghiorghes GJ designed, wrote and edited the manuscript including all aspects on controversies, the mechanisms of iron chelation therapy and also iron metabolism and toxicity.

Correspondence to: George J Kontoghiorghes, PhD, Postgraduate Research Institute of Science, Technology, Environment and Medicine, 3 Ammochostou Street, Limassol 3021,

Telephone: +357-26-272076



Iron is essential for all organisms including microbial, cancer and human cells. More than a quarter of the human population is affected by abnormalities of iron metabolism, mainly from iron deficiency and iron overload. Iron also plays an important role in free radical pathology and oxidative damage which is observed in almost all major diseases, cancer and ageing. New developments include the complete treatment of iron overload and reduction of morbidity and mortality in thalassaemia using deferiprone and selected deferiprone/deferoxamine combinations and also the use of the maltol iron complex in the treatment of iron deficiency anaemia. There is also a prospect of using deferiprone as a universal antioxidant in non iron overloaded diseases such as neurodegenerative, cardiovascular, renal, infectious diseases and cancer. New regulatory molecules of iron metabolism such as endogenous and dietary chelating molecules, hepcidin, mitochondrial ferritin and their role in health and disease is under evaluation. Similarly, new mechanisms of iron deposition, removal, distribution and toxicity have been identified using new techniques such as magnetic resonance imaging increasing our understanding of iron metabolic processes and the targeted treatment of related diseases. The uniform distribution of iron in iron overload between organs and within each organ is no longer valid. Several other controversies such as the toxicity impact of non transferrin bound iron vs injected iron, the excess levels of iron in tissues causing toxicity and the role of chelation on iron absorption need further investigation. Commercial interests of pharmaceutical companies and connections to leading journals are playing a crucial role in shaping worldwide medical opinion on drug sales and use but also patients’ therapeutic outcome and safety. Major controversies include the selection criteria and risk/benefit assessment in the use of deferasirox in thalassaemia and more so in idiopathic haemochromatosis, thalassaemia intermedia and ex-thalassaemia transplanted patients who are safely treated with venesection. Iron chelating drugs can override normal regulatory pathways, correct iron imbalance and minimise iron toxicity. The use of iron chelating drugs as main, alternative or adjuvant therapy is in progress in many conditions, especially those with non established or effective therapies.




Clinical Experience With Deferiprone Treatment for Friedreich Ataxia

1.  Sandra Elincx-Benizri1,*

2.  Amir Glik2,*

3.  Drorit Merkel3,4

4.  Michael Arad4,5

5.  Dov Freimark4,5

6.  Evgenia Kozlova1

7.  Ioav Cabantchik6

8.  Sharon Hassin-Baer1,4

1.   1Movement Disorders Institute, Department of Neurology, Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel

2.   2Cognitive Neurology Clinic and Department of Neurology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel

3.   3Division of Hematology, Chaim Sheba Medical Center, Ramat-Gan, Israel

4.   4Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

5.   5Leviev Heart Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat-Gan, Israel

6.   6Department of Biological Chemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem Givat Ram, Jerusalem, Israel

7.   *Both authors contributed equally to the article

1.   Sharon Hassin-Baer, Parkinson Disease and Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel- Hashomer, Ramat Gan 52621001, Israel. Email:


Friedreich ataxia is an inherited disorder characterized by degeneration of the peripheral and central nervous system and hypertrophic cardiomyopathy. Homozygous mutations in the frataxine (FXN) gene reduce expression of frataxin and cause accumulation of iron in the mitochondria. Deferiprone, an oral iron chelator, has been shown effective in cell and animal models of Friedreich ataxia. The results of a 6-month randomized, double blind placebo-controlled study suggested that deferiprone 20 mg/kg/day may reduce disease progression. The authors present their experience of 5 Friedreich ataxia patients treated with deferiprone (20 mg/kg/day), in addition to idebenone treatment, followed over a period of 10-24 months, under off-label authorization. The patients were monitored for laboratory parameters, cardiac assessment, neurological evaluations, and quality of life. The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.



Assessment and management of cavus foot deformity

J. Grice


 H. Willmott


 H. Taylor

John E Grice MBBS MRCS (Lond) MSc SEM FRCS (Tr & Orth) Fellow in Foot & Ankle Surgery, Orthopaedic Department, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Castle Lane East, Bournemouth, UK. Conflict of interest: none

Heath Taylor MBBS BSc FRCS (Tr & Orth) Consultant Orthopaedic Surgeon, Orthopaedic Department, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Castle Lane East, Bournemouth, UK. Conflict of interest: none

Henry Willmott BMBS BMedSci(Hons) MSc FRCS (Tr & Orth) Consultant Orthopaedic Surgeon, Orthopaedic Department, Conquest Hospital, East Sussex Healthcare NHS Trust, The Ridge, St Leonards-on-Sea, East Sussex, UK. Conflict of interest: none


The cavus foot, or pes cavus, is a deformity of the foot characterised by a high longitudinal arch. It is classically associated with neurological conditions and muscle imbalance. The deformity varies in severity and can affect any or all of the hindfoot, midfoot or forefoot. Careful examination should be performed and underlying neurological conditions sought. We outline an á la carte approach to surgical management, in which deformity of the ankle and hindfoot is addressed before moving on to assessment and correction of the mid- and forefoot. Flexible deformities can be corrected with ligament rebalancing and osteotomies whereas fixed deformity frequently requires arthrodesis. Dynamic muscle equilibrium should always be re-established using appropriate tendon transfers.




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