Paying for future success in gene therapy

Stuart H. Orkin, Philip Reilly. Science 27 May 2016: Vol. 352, Issue 6289, pp. 1059-1061 DOI: 10.1126/science.aaf4770

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The authors expect the federal Food and Drug Administration (FDA) will approve at least one gene therapy treatment within the next three years. As a new generation of gene therapy clinical trials shows promise to cure or halt the progression of several rare diseases, the time has come to explore ways to pay for the cutting edge treatments. Noting the potential of gene therapy to be a one-time treatment for rare and serious diseases that otherwise cost hundreds of thousands, if not millions, of dollars in chronic care over a lifetime. The process of developing a new gene therapy treatment and securing FDA approval, they estimate, entails about eight years and direct costs of hundreds of millions of dollars.

Uncovering brain-heart information through advanced signal and image processing.

Philos Trans A Math Phys Eng Sci. 2016 May 13; 374(2067): 20160020. doi: 10.1098/rsta.2016.0020


A recent article in Scientific American (‘A new idea for treating Alzheimer's’)begins with the following sentence: ‘If it's good for the heart, it could also be good for the neurons, astrocytes and oligodendrocytes, cells that make up the main items on the brain's parts list’, suggesting that Alzheimer's disease may be a candidate for combined brain–heart therapeutic approaches. Furthermore, a wide variety of changes in the electrocardiogram, mainly referring to arrhythmias and repolarization, is often observed in the context of neurological disease.
A significant part of the current knowledge on brain–heart interaction as applied to the medical field refers to ‘neurocardiology’. While this discipline is inherently multidimensional, it may be conceptualized as divided into three major categories: the heart's effects on the brain (e.g. cardiac source embolic stroke), the brain's effects on the heart (e.g. neurogenic heart disease) and neurocardiac syndromes (e.g. Friedreich's ataxia).

Open Access
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Inside HDACs with more selective HDAC inhibitors

Joëlle Roche, Philippe Bertrand, European Journal of Medicinal Chemistry, Available online 25 May 2016, ISSN 0223-5234, doi: 10.1016/j.ejmech.2016.05.047.

Inhibitors of histone deacetylases (HDACs) are nowadays part of the therapeutic arsenal mainly against cancers, with four compounds approved by the Food and Drug Administration.During the last five years, several groups have made continuous efforts to improve this class of compounds, designing more selective compounds or compounds with multiple capacities. After a survey of the HDACs biology and structures, this review summarizes the results of the chemists working in this field, and highlights when possible the behaviour of the molecules inside their targets.

Associated disease: Friedreich's ataxia. Partners: Interacts with HDAC7 and HDAC9; DAXX, HDAC10 and DACH1; BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY, BTBD14B, GLIS2, NR2C1; CBFA2T3 and NKAP; APEX1, MAPK14, ZMYND15, SMRT/NCOR2 and BCL6, INSM1, XBP1 isoform 1, CCAR2, MEF2D, BEND3. Forms a heterologous complex at least with YY1, It may participate in the regulation of transcription through its binding with the zinc-finger transcription factor YY1. Found in a complex with NCOR1 and NCOR2. Component of the N-Cor repressor complex. Component of the Notch corepressor complex. Functions: This protein can also down-regulate p53 function and thus modulate cell growth and apoptosis. This gene is regarded as a potential tumour suppressor gene.

Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia

R Abeti, M H Parkinson, I P Hargreaves, P R Angelova, C Sandi, M A Pook, P Giunti and A Y Abramov. Cell Death and Disease (2016) 7, e2237; doi:10.1038/cddis.2016.111 Published online 26 May 2016

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Although the role of frataxin is largely known, being fundamental for the iron biogenesis in the cell, the relation between frataxin and mitochondrial bioenergetics is not completely clear.

We assessed the type of mitochondrial dysfunction that was present in the cerebellum, concluding that Complex I activity is impaired, but Complex II compensates by overworking. Therefore, if we consider the ETC, we can define the mitochondrial dysfunction as a mildly defective bioenergetic phenotype. However, this mild dysfunction drives the formation of free radicals that cannot be attenuated by the endogenous antioxidant systems, which are downregulated. Thus, the level of lipid peroxidation increases dramatically, damaging the cells and causing premature cell death. Therefore, lipid peroxidation could be a potential target for future therapeutic approaches in FRDA.

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

Mugdha Joshi, Irina Anselm, Jiahai Shi, Tejus A. Bale, Meghan Towne, Klaus Schmitz-Abe, Laura Crowley, Felix C. Giani, Shideh Kazerounian, Kyriacos Markianos, Hart G. Lidov, Rebecca Folkerth, Vijay G. Sankaran, and Pankaj B. Agrawal. Cold Spring Harb Mol Case Stud. 2016 May; 2(3): a000786. doi:10.1101/mcs.a000786


This study describes a severe mitochondrial disease due to PMPCA mutations in a large family, which we show is associated with altered levels of mature frataxin. Whereas a recent study described cerebellar ataxia as a presentation of PMPCA mutations, the phenotype in our family is more severe and typical of a mitochondrial disease. The observed phenotype may be related to impaired PMPCA function due to a reduction in its level and the resultant abnormal processing of frataxin and other mitochondrial proteins.

Open Access
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JOT101, a product for treatment of Friedreich’s ataxia.

Jupiter, Florida (PRWEB) May 25, 2016, by Christer Rosén, Jupiter Orphan Therapeutics.

Jupiter Orphan Therapeutics, Inc. (JOT) today announced that world renowned scientist David Sinclair, Ph.D. joined JOT as Co-Chairman of its Scientific Advisory Board (SAB).

Dr. Sinclair was contacted by his fellow scientists, Prof Martin Delatycki from Murdoch Childrens Research Institute, Australia (MCRI), who informed him of the resveratrol JOTROL product that was developed by JOT. JOT has a global license from MCRI regarding developing JOT101, a product for treatment of Friedreich’s ataxia.

Dr. Sinclair stated “I am excited about being able to work with JOT to bring drugs to patients who are waiting for a solution to their rare disease. JOTROL opens up the possibility that resveratrol will finally realize its potential to revolutionize human health.”

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

Kevin C. Kemp, Amelia J. Cook, Juliana Redondo, Kathreena M. Kurian, Neil J. Scolding and Alastair Wilkins. Acta Neuropathologica CommunicationsNeuroscience of Disease20164:53. DOI: 10.1186/s40478-016-0326-3

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.

Understanding whether Purkinje cell axon remodelling and/or fusion represent mechanisms by which cerebellar functions can be maintained in genetic cerebellar disease has important therapeutic consequences. With the potential to protect and rescue neuronal cells and restore homeostatic balance during neurodegeneration, understanding the circumstances in which they occur may lead to techniques to manipulate these mechanisms therapeutically.

Open Access.
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://​creativecommons.​org/​licenses/​by/​4.​0/​)

Longitudinal strain bull's eye plot patterns in patients with cardiomyopathy and concentric left ventricular hypertrophy.

Dan Liu, Kai Hu, Peter Nordbeck, Georg Ertl, Stefan Störk and Frank Weidemann. European Journal of Medical Research 201621:21 DOI: 10.1186/s40001-016-0216-y

Friedreich’s ataxia: Besides the neurologic manifestation, cardiac involvement and endocrine involvement are also frequent. A concentric LVH with an end-diastolic wall thickness of less than 15 mm is the usual echocardiographic feature. Around 40 % of FA patients show concentric remodeling, 35 % show concentric hypertrophy and only 5 % display an eccentric hypertrophy. Global systolic function and diastolic function remain normal in most FA patients, and only end-stage FA patients develop reduced EF with global hypokinesia and slightly dilated LV chamber.

Electrocardiographic abnormalities (ST-T changes) are often the earliest sign of FA cardiomyopathy. At this early stage, echocardiography results are usually normal and the longitudinal strain bull’s eye plot is similar pattern as healthy subjects (Fig. 7a). In FA patients with concentric LVH and normal EF, the bull’s eye plot pattern presents with a mildly reduced average global strain (Fig. 7b). Myocardial fibrosis develops gradually, leading to LV wall thinning and LV dilatation during the disease progression, while EF remains preserved for a long time until the end-stage of the disease. Of note, the LV wall thinning appears to be diffuse in FA cardiomyopathy, which is different from the typical findings in Fabry cardiomyopathy. The bull’s eye plot shows significantly reduced average global longitudinal strain when LVEF is reduced (Fig. 7c).

CMRI with LE imaging provides evidence of fibrosis in the advanced stage of this disease, suggesting that fibrosis might be associated with subsequent myocardial dysfunction.

Open Access
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Role of XPD in cellular functions: to TFIIH and beyond

Bennett Van Houten, Jochen Kuper, Caroline Kisker, DNA Repair, Available online 16 May 2016, ISSN 1568-7864, doi: 10.1016/j.dnarep.2016.05.019.

One interesting implication of this work is in cells deficient in iron-sulfur cluster biogenesis, such as those from patients with Friedreich ataxia (FA), since several key DNA processing proteins, such as XPD, DDX11, FANCJ and RTEL1 contain FeS centers, these patients displayed an RNA expression pattern similar to cells undergoing a DNA damage respons. FA patients might be expected to have higher levels of DNA damage. It has recently been observed that these patients have altered telomeres because RTEL1 activity is lower.

The epidemiology of neuromuscular disorders: Age at onset and gender in the Netherlands

Johanna C.W. Deenen, Pieter A. van Doorn, Catharina G. Faber, Anneke J. van der Kooi, Jan B.M. Kuks, Nicolette C. Notermans, Leo H. Visser, Corinne G.C. Horlings, Jan J.G.M. Verschuuren, André L.M. Verbeek, Baziel G.M. van Engelen, Neuromuscular Disorders, Available online 21 April 2016, ISSN 0960-8966, doi:10.1016/j.nmd.2016.04.011

Based on approximately eight years of data collection with the nationwide Computer Registry of All Myopathies and Polyneuropathies (CRAMP) in the Netherlands, recent epidemiologic information for thirty neuromuscular disorders is presented. Friedreich's Ataxia is included. These data may be helpful in the diagnostic process in clinical practice and trial readiness.

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

18 May 2016 | Marketwired.

"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"

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.

Movimientos anormales y embarazo / Abnormal movements and pregnancy

Eduardo Palacios, Ángela Viviana Navas, Repertorio de Medicina y Cirugía, Available online 30 April 2016, ISSN 0121-7372, doi:10.1016/j.reper.2016.04.001.

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Los estudios en este grupo de pacientes son escasos y antiguos dada la baja prevalencia.
Las mujeres con FA tienen una supervivencia más larga que los hombres, lo cual permite más años potenciales de maternidad durante las etapas avanzadas de la enfermedad. En la mayor serie, las complicaciones maternas más significativas fueron cardiacas y endocrinas; sin embargo, la capacidad para llevar a término el embarazo no fue afectada ni se presentaron malformaciones congénitas.

Mitochondrial disorders in children: toward development of small‐molecule treatment strategies

Werner JH Koopman, Julien Beyrath, Cheuk‐Wing Fung, Saskia Koene, Richard J Rodenburg, Peter HGM Willems, Jan AM Smeitink. EMBO Molecular Medicine (2016) 8, 311-327, DOI 10.15252/emmm.201506131

Review

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The Effect of Piracetam on Friedreich Ataxia.

Elmal AD , Gündüz A , Uzun N , Apaydn H , Kzltan G; Clinical Neuropharmacology [2016, 39(3):159-160] DOI: 10.1097/WNF.0000000000000148

Can other gene therapy developers avoid Glybera's fate?

FiercePharma, by Tracy Staton | May 4, 2016.

Glybera, the treatment for an ultra-rare disease called lipoprotein lipase deficiency approved back in 2012 in Europe, carries a price tag of $1 million.

GSK has said it won’t price its med anywhere close to $1 million. "We're trying to create a balance between nurturing innovation and creating value for the healthcare system,” spokeswoman Fiona McMillan told FiercePharma last month. “I know there are concerns about Europe's first gene therapy approval [Glybera] costing around $1 million, but I can say that Strimvelis will be significantly less than that.”

Responsible implementation of expanded carrier screening

Lidewij Henneman, Pascal Borry, Davit Chokoshvili, Martina C Cornel, Carla G van El, Francesca Forzano, Alison Hall, Heidi C Howard, Sandra Janssens, Hülya Kayserili, Phillis Lakeman, Anneke Lucassen, Sylvia A Metcalfe, Lovro Vidmar, Guido de Wert, Wybo J Dondorp and Borut Peterlin on behalf of the European Society of Human Genetics (ESHG), European Journal of Human Genetics (2016) 24, e1–e12; doi:10.1038/ejhg.2015.271; published online 16 March 2016

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It is estimated that there are more than 1300 recessively inherited disorders (autosomal and X-linked), whose symptoms range from the very mild to severe, cumulatively affecting at least 30 in every 10000 children. This means that approximately 1–2 in 100 couples are couples who are at risk of having a child affected with a recessive genetic condition. Only a minority of carrier couples will be identified, since the majority of affected children are born to couples with no previous known family history, and only a minority of relatives in high-risk families request carrier testing.

Advances in management of movement disorders in children

Anne Koy, Jean-Pierre Lin, Terence D Sanger, Warren A Marks, Jonathan W Mink, Lars Timmermann, The Lancet Neurology, Volume 15, Issue 7, June 2016, Pages 719-735, ISSN 1474-4422, doi:10.1016/S1474-4422(16)00132-0

Movement disorders in children are causally and clinically heterogeneous and present in a challenging developmental context. Treatment options are broad ranging, from pharmacotherapy to invasive neuromodulation and experimental gene and stem cell therapies.It is vital to transfer the expanding knowledge of the movement disorders into the development of novel symptomatic or, ideally, disease-modifying treatments, and to assess these therapeutic strategies in appropriately designed and well done trials.

Iron chelation in the treatment of neurodegenerative diseases.

Dusek P, Schneider SA, Aaseth J. J Trace Elem Med Biol. 2016 Mar 24. pii: S0946-672X(16)30047-5. doi: 10.1016/j.jtemb.2016.03.010.

Several studies examining effect of chelation therapy in Friedreich’s ataxia have been conducted. Higher doses of deferiprone seem to worsen neurologic symptoms in FRDA; lower doses might be beneficial in younger patients with less severe disease. However, more evidence is needed.

Translation of Human-Induced Pluripotent Stem Cells: From Clinical Trial in a Dish to Precision Medicine

Nazish Sayed, Chun Liu, Joseph C. Wu, Journal of the American College of Cardiology, Volume 67, Issue 18, 10 May 2016, Pages 2161-2176, ISSN 0735-1097, doi:10.1016/j.jacc.2016.01.083.

Human-induced pluripotent stem cells (iPSCs) provide a new source of therapeutic cells free from the ethical issues or immune barriers of human embryonic stem cells. iPSC technology has expanded with 3 major applications: disease modeling, regenerative therapy, and drug discovery. Here we discuss, in a comprehensive manner, the recent advances in iPSC technology in relation to basic, clinical, and population health.

Constrictive Pericarditis Versus Restrictive Cardiomyopathy?

Mario J. Garcia, Journal of the American College of Cardiology, Volume 67, Issue 17, 3 May 2016, Pages 2061-2076, ISSN 0735-1097, doi:10.1016/j.jacc.2016.01.076.


Friedreich’s ataxia is an autosomal recessive neurodegenerative disorder. Ventricular arrhythmias and SCD are common. Early in the course of the disease, ECG and echocardiographic findings resemble those of hypertrophic cardiomyopathy, including symmetric LV hypertrophy, abnormal myocardial relaxation, and LV outflow obstruction. Over time, the restrictive phenotype evolves into a dilated phenotype. There is no specific treatment for this condition other than standard HF drugs. Implantable cardioverter-defibrillators are used for prevention of SCD, but a survival benefit has not been demonstrated.

Horizon Pharma plc Completes Target Enrollment of 90 Patients for Phase 3 Trial of ACTIMMUNE(R) (interferon gamma-1b) for the Treatment of People With Friedreich's Ataxia

DUBLIN, IRELAND -- (Marketwired) -- 05/05/16 -- Horizon Pharma plc today announced that it has completed target enrollment of its Phase 3 study evaluating ACTIMMUNE (interferon gamma-1b) for the treatment of people with Friedreich's ataxia (FA). The study (NCT02415127) has reached its target enrollment of 90 patients at four sites in the United States, and top-line results are expected by the end of 2016.

The Safety, Tolerability and Efficacy of ACTIMMUNE Dose Escalation in Friedreich's Ataxia study ("STEADFAST") is a randomized, multi-center, double-blind, placebo-controlled study with patients randomized 1:1 to receive subcutaneous doses of either ACTIMMUNE or placebo three times a week for a total of 26 weeks. After completion of the study, patients who participated in STEADFAST will have the opportunity to transition to an open-label extension study (NCT02593773).

Patent Granted for RNA Transcription Technology

Science & Enterprise, By Alan, on May 3rd, 2016.

3 May 2016. A technology that blocks RNA molecules from activating chemicals in the body suppressing the working of genes to treat or prevent disease received a U.S. patent. The technology was licensed to RaNA Therapeutics in Cambridge, Massachusetts, co-founded by lead inventor Jeannie Lee, a professor of genetics and pathology at Mass. General and Harvard Medical School.

The first therapies under development are treatments for the rare central nervous system disorders spinal muscular atrophy and Friedreich’s ataxia, both programs are still in preclinical stages.

Dorsal root ganglia in Friedreich ataxia: satellite cell proliferation and inflammation

Arnulf H. Koeppen, R. Liane Ramirez, Alyssa B. Becker and Joseph E. Mazurkiewicz. Acta Neuropathologica Communications, Neuroscience of Disease 20164:46 DOI: 10.1186/s40478-016-0288-5

We conclude that FA differentially affects the key cellular elements of DRG, and postulate that the disease causes loss of bidirectional trophic support between satellite cells and neurons.

Mitochondrial dysfunction and cell death in neurodegenerative diseases through nitroxidative stress

Mohammed Akbar, Musthafa Mohamed Essa, Ghazi Daradkeh, Mohamed A. Abdelmegeed, Youngshim Choi, Lubna Mahmood, Byoung-Joon Song, Brain Research, Available online 13 February 2016, ISSN 0006-8993, doi:10.1016/j.brainres.2016.02.016.

This review 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, Clinical Science Apr 22, 2016, 130 (11) 853-870; DOI: 10.1042/CS20160072

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

Mawi DNA Technologies / News. April 27, 2016

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.