GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one

Anasheh Halabi Kayla T B Fuselier Ed Grabczyk. Nucleic Acids Research, gky143, doi:10.1093/nar/gky143

DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism. MutSβ has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear. Here we show that MutLγ (MLH1-MLH3) is the MutL complex responsible for GAA•TTC repeat expansion. Lentiviral expression of shRNA targeting MutL nuclease components MLH1, PMS2, and MLH3 revealed that reduced expression of MLH1 or MLH3 reduced the repeat expansion rate in a human Friedreich ataxia cell model, while targeting PMS2 did not. Using splice-switching oligonucleotides we show that MLH3 isoform 1 is active in GAA•TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not. MLH3 isoform switching slowed repeat expansion in both model cells and FRDA patient fibroblasts. Our work indicates a specific and active role for MutLγ in the expansion process and reveals plausible targets for disease-modifying therapies.

BMN 290 for Friedreich's Ataxia

News provided by BioMarin Pharmaceutical Inc.; SAN RAFAEL, Calif., Feb. 22, 2018 /PRNewswire/

In the fourth quarter of 2017, BioMarin announced that it had selected as its next drug development candidate, BMN 290, a selective chromatin modulation therapy intended for treatment of Friedreich's ataxia. Friedreich's ataxia is a rare autosomal recessive disorder that results in disabling neurologic and cardiac progressive decline. Prior to the compound being acquired by BioMarin from Repligen Corporation (Repligen), it demonstrated increases in frataxin in Friedreich's ataxia patients. In preclinical models, BMN 290 increases frataxin expression in brain tissues more than two-fold. The Company selected BMN 290 for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. Currently, there are no approved disease modifying therapies for Friedreich's ataxia. The Company expects to submit the IND application for BMN 290 in the second half of 2018.

Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier

Blake H. Albright, Claire M. Storey, Giridhar Murlidharan, Ruth M. Castellanos Rivera, Garrett E. Berry, Victoria J. Madigan, Aravind Asokan; Molecular Therapy, Volume 26, Issue 2, p510–523, 7 February 2018 DOI: 10.1016/j.ymthe.2017.10.017

Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.

Hepcidin, an emerging and important player in brain iron homeostasis

Driton Vela. Journal of Translational Medicine 201816:25 doi:10.1186/s12967-018-1399-5

Iron dysregulation has been observed consistently in different organs in Friedreich ataxia (FA). This disease affects CNS by causing neurodegenerative damages in dentate nuclei of the cerebellum, dorsal root ganglia, but also in cerebrum, thalamus and other structures. FA is caused by a defective frataxin, which main functions include involvement in iron-sulfur cluster formation and in iron delivery to ferrochelatase. Although some observations did find iron accumulation in dentate nuclei in FA patients, other studies have revealed a pattern of iron redistribution, rather than iron accumulation in FA. Studies suggest that iron dysregulation in FA is not needed for neurodegeneration to occur, while animal models reveal tissue-specific damages due to frataxin deficiency. These differences are related with levels of frataxin expression, where most of the damage is observed in tissues with higher expression of frataxin, such as the heart and dorsal root ganglia. In the heart, inflammatory infiltrate produces hepcidin and has been proposed as one of the pathogenic mechanisms of heart damage in FA. Frataxin deficiency in animal models can cause a strong inflammatory reaction in Schwann cells, which are known to enwrap neurons of dorsal root ganglia. These neurons are frequently affected in FA and are characterized with iron dysregulation and inappropriate myelination. But, hepcidin expression in these cells has not been studied in models of FA, therefore it is not known what role, if any, does hepcidin have in the pathophysiology of neurodegeneration in FA.

Perceived Fatigue and Energy are Independent Unipolar States: Supporting Evidence

Bryan D. Loy, Michelle H. Cameron, Patrick J. O'Connor, Medical Hypotheses, Available online 19 February 2018, ISSN 0306-9877, doi:10.1016/j.mehy.2018.02.014.

Persistent fatigue is a common problem (∼20-45% of U.S. population), with higher prevalence and severity in people with medical conditions such as cancer, depression, fibromyalgia, heart failure, sleep apnea and multiple sclerosis. There are few FDA-approved treatments for fatigue and great disagreement on how to measure fatigue, with over 250 instruments used in research. Many instruments define fatigue as “a lack of energy”, thus viewing energy and fatigue states as opposites on a single bipolar continuum. In this paper, we hypothesize that energy and fatigue are distinct perceptual states, should be measured using separate unipolar scales, have different mechanisms, and deficits should be treated using tailored therapies. Energy and fatigue independence has been found in both exploratory and confirmatory factor analysis studies. Experiments in various fields, including behavioral pharmacology and exercise science, often find changes in energy and not fatigue, or vice versa. If the hypothesis that energy and fatigue are independent is correct, there are likely different mechanisms that drive energy and fatigue changes. Energy could be increased by elevated dopamine and norepinephrine transmission and binding. Fatigue could be increased by elevated brain serotonin and inflammatory cytokines and reduced histamine binding. The hypothesis could be tested by an experiment that attempts to produce simultaneously high ratings of energy and fatigue (such as with two drugs using a randomized, double-blind, placebo-controlled design), which would offer strong evidence against the common viewpoint of a bipolar continuum. If the hypothesis is correct, prior literature using bipolar instruments will be limited, and research on the prevalence, mechanisms, and treatment of low energy and elevated fatigue as separate conditions will be needed. In the immediate future, measuring both energy and fatigue using unipolar measurement tools may improve our understanding of these states and improve therapeutic outcomes.
When mental and physical aspects of energy and fatigue were measured in individuals with Friedreich’s ataxia, low physical energy was found while no differences were observed for mental energy or mental or physical fatigue. This type of information appears logical and is potentially useful because Friedreich’s ataxia is a disease that targets pyramidal nerves, causing muscle incoordination and reduced physical activity that worsens over time yet largely preserves mental functioning.

Progress in the treatment of Friedreich ataxia

Geneieve Tai, Louise A. Corben, Eppie M. Yiu, Sarah C. Milne, Martin B. Delatycki, Neurologia i Neurochirurgia Polska, Available online 19 February 2018, ISSN 0028-3843, doi:10.1016/j.pjnns.2018.02.003.

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA.

Meet Our Scientists. Ernest Giralt: "There are many diseases caused by failures in the protein-protein interactions”

IRB Barcelona, Institutional news. 14 Feb 2018

The Meet Our Scientists series presents Ernest Giralt, doctor of chemical sciences, who is the head of the Peptides and Proteins laboratory at IRB Barcelona.

In the video "The power of medicinal chemistry", Giralt highlights his interest in deciphering the language used by proteins to interact with each other.

The chemist Ernest Giralt (Viladecans, 1948) is the head of the Peptides and Proteins Laboratory at IRB Barcelona, ​​composed of more than 20 people among researchers and PhD students. This group focuses its research on peptides, small proteins, and on the dynamic properties of proteins.
Giralt has always been interested in trying to decipher the language that different proteins use to interact with each other, not only to unravel the biology of these interactions but also for their biomedical applicability since "there are many illnesses that are caused by errors in these interactions ".
The peptides designed in their laboratory are destined to interrupt or favour the unwanted interaction between the proteins. Among other advances, they have discovered some that interrupt very effectively an interaction between proteins related to cancer, which could open a door to new therapies against this disease. Likewise, they develop shuttle peptides that cross the blood-brain barrier to be able to supply drugs to the brain and that can be used for the treatment of pediatric brain cancer and for Friedrich's ataxia, a hereditary neurodegenerative disease.

Rules for processing genetic data for research purposes in view of the new EU General Data Protection Regulation

Mahsa Shabani & Pascal Borry; European Journal of Human Geneticsvolume 26, pages149–156 (2018) doi:10.1038/s41431-017-0045-7

Genetic data contain sensitive health and non-health-related information about the individuals and their family members. Therefore, adopting adequate privacy safeguards is paramount when processing genetic data for research or clinical purposes. One of the major legal instruments for personal data protection in the EU is the new General Data Protection Regulation (GDPR), which has entered into force in May 2016 and repealed the Directive 95/46/EC, with an ultimate goal of enhancing effectiveness and harmonization of personal data protection in the EU.
The new Regulation has already fueled concerns among various stakeholders, owing to the challenges that may emerge when implementing the Regulation across the countries. Notably, the provided definition for pseudonymized data has been criticized because it leaves too much room for interpretations, and it might undermine the harmonization of the data protection across the countries.

Low apolipoprotein A-I levels in Friedreich’s ataxia and in frataxin-deficient cells: Implications for therapy.

QingQing Wang, Lili Guo, Cassandra J. Strawser, Lauren A. Hauser, Wei-Ting Hwang, Nathaniel W. Snyder, David R. Lynch, Clementina Mesaros, Ian A. Blair. PLoS ONE 13(2): e0192779. doi:10.1371/journal.pone.0192779

Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.

Comprehensive systematic review summary: Treatment of cerebellar motor dysfunction and ataxia Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology

Theresa A. Zesiewicz, George Wilmot, Sheng-Han Kuo, Susan Perlman, Patricia E. Greenstein, Sarah H. Ying, Tetsuo Ashizawa, S.H. Subramony, Jeremy D. Schmahmann, K.P. Figueroa, Hidehiro Mizusawa, Ludger Schöls, Jessica D. Shaw, Richard M. Dubinsky, Melissa J. Armstrong, Gary S. Gronseth and Kelly L. Sullivan. Neurology published online February 9, 2018 doi:10.1212/WNL.0000000000005055

Objective To systematically review evidence regarding ataxia treatment.

Methods A comprehensive systematic review was performed according to American Academy of Neurology methodology.

Conclusions For patients with episodic ataxia type 2, 4-aminopyridine 15 mg/d probably reduces ataxia attack frequency over 3 months (1 Class I study). For patients with ataxia of mixed etiology, riluzole probably improves ataxia signs at 8 weeks (1 Class I study). For patients with Friedreich ataxia or spinocerebellar ataxia (SCA), riluzole probably improves ataxia signs at 12 months (1 Class I study). For patients with SCA type 3, valproic acid 1,200 mg/d possibly improves ataxia at 12 weeks. For patients with spinocerebellar degeneration, thyrotropin-releasing hormone possibly improves some ataxia signs over 10 to 14 days (1 Class II study). For patients with SCA type 3 who are ambulatory, lithium probably does not improve signs of ataxia over 48 weeks (1 Class I study). For patients with Friedreich ataxia, deferiprone possibly worsens ataxia signs over 6 months (1 Class II study). Data are insufficient to support or refute the use of numerous agents. For nonpharmacologic options, in patients with degenerative ataxias, 4-week inpatient rehabilitation probably improves ataxia and function (1 Class I study); transcranial magnetic stimulation possibly improves cerebellar motor signs at 21 days (1 Class II study). For patients with multiple sclerosis–associated ataxia, the addition of pressure splints possibly has no additional benefit compared with neuromuscular rehabilitation alone (1 Class II study). Data are insufficient to support or refute use of stochastic whole-body vibration therapy (1 Class III study).