Tuesday, February 27, 2018

Commentary: Novelty Seeking and Reward Dependence-Related Large-Scale Brain Networks Functional Connectivity Variation During Salience Expectancy

Cristiano Crescentini. Front. Psychol. doi: 10.3389/fpsyg.2018.00242 (General Commentary ARTICLE Provisionally accepted, The full-text will be published soon)

In recent years several neuropsychological and psychiatry studies employed the psychobiological model of temperament and character to investigate the relationship between personality and neuropsychological function in patients with Parkinson’s disease, Friedreich Ataxia, attention-deficit/hyperactivity disorder, eating disorders, and antisocial behavior.
These studies indicated that alterations in personality and cognition are not independent from each other, in that poor development of specific personality traits appears to be associated with deficits in neuropsychological performance, in particular in advanced cognition such as executive functions.

Monday, February 26, 2018

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.

Friday, February 23, 2018

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.

Thursday, February 22, 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.

Wednesday, February 21, 2018

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.

Tuesday, February 20, 2018

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.

Friday, February 16, 2018

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.

Thursday, February 15, 2018

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).

Interactions of Frataxin with ISCU and Ferredoxin on the Cysteine Desulfurase Complex Leading to Fe-S Cluster Assembly

Kai Cai. Volume 114, Issue 3, Supplement 1, 2 February 2018, Pages 571a, doi:10.1016/j.bpj.2017.11.3123

Frataxin (FXN) is involved in mitochondrial iron-sulfur (Fe-S) cluster biogenesis and serves to accelerate Fe-S cluster formation. FXN deficiency is associated with Friedreich ataxia, a neurodegenerative disease. We have used a combination of isothermal titration calorimetry, chemical cross-linking with analysis by LC/MS/MS, multinuclear NMR spectroscopy, and biochemical assays to investigate interactions among the components of the biological machine that carries out the assembly of iron-sulfur clusters in human mitochondria. We have constructed a structural model of the core of this machine by combining homology modeling with docking constraints derived from NMR chemical shift perturbations and chemical cross-linking studies. We show that the machinery operates through dynamic interactions among its components and have identified interactions relevant to the cysteine desulfurase reaction, which generates S, and iron transfer from FXN, which leads to iron-sulfur cluster assembly. We also have elucidated the mechanism by which the variant ISCU(M108I) bypasses the requirement for FXN.

RNA–DNA hybrids promote the expansion of Friedreich's ataxia (GAA)n repeats via break-induced replication

Alexander J Neil Miranda U Liang Alexandra N Khristich Kartik A Shah Sergei M Mirkin; Nucleic Acids Research, , gky099, doi:10.1093/nar/gky099

Expansion of simple DNA repeats is responsible for numerous hereditary diseases in humans. The role of DNA replication, repair and transcription in the expansion process has been well documented. Here we analyzed, in a yeast experimental system, the role of RNA–DNA hybrids in genetic instability of long (GAA)n repeats, which cause Friedreich’s ataxia. Knocking out both yeast RNase H enzymes, which counteract the formation of RNA–DNA hybrids, increased (GAA)n repeat expansion and contraction rates when the repetitive sequence was transcribed. Unexpectedly, we observed a similar increase in repeat instability in RNase H-deficient cells when we either changed the direction of transcription-replication collisions, or flipped the repeat sequence such that the (UUC)n run occurred in the transcript. The increase in repeat expansions in RNase H-deficient strains was dependent on Rad52 and Pol32 proteins, suggesting that break-induced replication (BIR) is responsible for this effect. We conclude that expansions of (GAA)n repeats are induced by the formation of RNA–DNA hybrids that trigger BIR. Since this stimulation is independent of which strand of the repeat (homopurine or homopyrimidine) is in the RNA transcript, we hypothesize that triplex H-DNA structures stabilized by an RNA–DNA hybrid (H-loops), rather than conventional R-loops, could be responsible.

Tuesday, February 13, 2018

Restless legs syndrome and periodic leg movements in patients with movement disorders: Specific considerations

Högl, B. and Stefani, A. (2017), Mov. Disord., 32: 669–681. doi: 10.1002/mds.26929

The diagnostic criteria for restless legs syndrome (RLS) have been continuously updated in recent years, considerably facilitating both an accurate diagnosis and appropriate management of RLS.
Periodic leg or limb movements during sleep (PLMS) are present in patients with and without RLS and can be seen as biomarkers of genetic susceptibility to RLS.
Restless legs syndrome, and eriodic leg movements during wakefulness (PLMW) were significantly higher in Friedrich’s ataxia patients with RLS than in those without. Interestingly, in most of them RLS onset was after Friedreich’s ataxia onset, and Friedreich’s ataxia patients with RLS had significantly lower ferritin levels than those without.
Substantia nigra echogenicity correlated inversely with disease severity of Friedrich’s ataxia and was significantly associated with RLS. In contrast, few Friedreich’s ataxia patients fulfilled RLS criteria.
Although the large variation of RLS frequencies reported in these patients could indicate diagnostic difficulties because of confounding symptoms, the apparent high frequency of RLS in Frie-
dreich’s ataxia and the association with disturbed brain iron metabolism is interesting and requires further study.

Wednesday, February 7, 2018

New Approaches to Exciting Exergame-Experiences for People with Motor Function Impairments

Eckert, M.; Gómez-Martinho, I.; Meneses, J.; Martínez, J.-F.; Sensors 2017, 17, 354. doi:10.3390/s17020354             
OPEN ACCESS

The work presented here suggests new ways to tackle exergames for physical rehabilitation and to improve the players’ immersion and involvement. The primary (but not exclusive) purpose is to increase the motivation of children and adolescents with severe physical impairments, for doing their required exercises while playing. The proposed gaming environment is based on the Kinect sensor and the Blender Game Engine. A middleware has been implemented that efficiently transmits the data from the sensor to the game. Inside the game, different newly proposed mechanisms have been developed to distinguish pure exercise-gestures from other movements used to control the game (e.g., opening a menu). The main contribution is the amplification of weak movements, which allows the physically impaired to have similar gaming experiences as the average population. To test the feasibility of the proposed methods, four mini-games were implemented and tested by a group of 11 volunteers with different disabilities, most of them bound to a wheelchair. Their performance has also been compared to that of a healthy control group. Results are generally positive and motivating, although there is much to do to improve the functionalities. There is a major demand for applications that help to include disabled people in society and to improve their life conditions. This work will contribute towards providing them with more fun during exercise.

ISCU(M108I) and ISCU(D39V) differ from wild type ISCU in their failure to form cysteine desulfurase complexes containing both frataxin and ferredoxin

Kai Cai, Ronnie O. Frederick, Marco Tonelli, and John L. Markley; Biochemistry, Just Accepted Manuscript DOI: 10.1021/acs.biochem.7b01234

Whereas iron-sulfur (Fe-S) cluster assembly on the wild-type scaffold protein ISCU, as catalyzed by the human cysteine desulfurase complex (SDA), exhibits a requirement for frataxin (FXN), assembly on variant ISCU(M108I) has been shown to bypass the FXN requirement. Wild-type ISCU populates two interconverting conformational states: one structured and one dynamically disordered. We show here that ISCU(M108I) populates only the structured state as does another variant ISCU(D39V). We have compared the properties ISCU, ISCU(M108I), and ISCU(D39V), with and without FXN, in both the cysteine desulfurase step of Fe-S cluster assembly and in the overall Fe-S cluster assembly reaction. In the cysteine desulfurase step with DTT as the reductant, FXN was found to stimulate cluster assembly with both the wild-type and structured variants, although the effect was less prominent with ISCU(D39V) than with wild-type or ISCU(M108I). In overall Fe-S cluster assembly, frataxin was found to stimulate cluster assembly with both the wild-type and structured variants when the reductant was DTT; however, with the physiological reductant, reduced ferredoxin 2 (rdFDX2), frataxin stimulated the reaction with wild-type ISCU but not with the fully-structured variants. Through NMR titration experiments, we discovered that, wild-type ISCU, frataxin, and rdFDX2 all bind to SDA. However, when ISCU was replaced by the fully-structured variant ISCU(M108I), the addition of rdFDX2 to the SDA-ISCU(M108I)-FXN complex led to the release of FXN. Thus, the displacement of FXN by rdFDX2 explains the failure of FXN to stimulate Fe-S cluster assembly on ISCU(M108I).

Tuesday, February 6, 2018

Idebenone: Novel Strategies to Improve Its Systemic and Local Efficacy

Lucia Montenegro, Rita Turnaturi, Carmela Parenti and Lorella Pasquinucci; Nanomaterials 2018, 8(2), 87; doi:10.3390/nano8020087

The key role of antioxidants in treating and preventing many systemic and topical diseases is well recognized. One of the most potent antioxidants available for pharmaceutical and cosmetic use is Idebenone (IDE), a synthetic analogue of Coenzyme Q10. Unfortunately, IDE’s unfavorable physicochemical properties such as poor water solubility and high lipophilicity impair its bioavailability after oral and topical administration and prevent its parenteral use. In recent decades, many strategies have been proposed to improve IDE effectiveness in the treatment of neurodegenerative diseases and skin disorders. After a brief description of IDE potential therapeutic applications and its pharmacokinetic and pharmacodynamic profile, this review will focus on the different approaches investigated to overcome IDE drawbacks, such as IDE incorporation into different types of delivery systems (liposomes, cyclodextrins, microemulsions, self-micro-emulsifying drug delivery systems, lipid-based nanoparticles, polymeric nanoparticles) and IDE chemical modification. The results of these studies will be illustrated with emphasis on the most innovative strategies and their future perspectives.

Monday, February 5, 2018

Jotrol IND Application Submission for MPS and Friedrich's Ataxia Imminent

Mathew Shanley, Rare Disease Report. FEBRUARY 05, 2018

Jupiter Orphan Therapeutics, Inc. (JOT) announced this morning that it intends to submit an Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA) for Jotrol in mucopolysaccharidosis type 1 (MPS I), among other indications, within the next few weeks.
"We will initiate the IND in MPS I and plan to cross-reference PK and safety data in follow-on indications. We are well prepared to gear up for a study in Friedreich's Ataxia (FA) and will thereafter determine if Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) or Leber's Hereditary Optic Neuropathy (LHON) will be the 3rd indication we approach. An IND submission for FA is planned for quarter 2 of 2018, and for MELAS and/or LHON no later than quarter 4," stated JOT Chief Security Officer Dr. Marshall Hayward in a press release.
JOT has used an isomer of the resveratrol to develop a pharmaceutical grade compound that can be properly tested in clinical trials, and successful pre-clinical data have shown that it can increase levels of frataxin.

To study the genotype - phenotype correlation of Friedreich’s Ataxia (FRDA) patients in Indian population

I. Ahmad, A. Kumar Srivastava, M. Faruq, V. Padma Srivastava M., Parkinsonism & Related Disorders, Volume 46, Supplement 2, January 2018, Page e7, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.11.023.

This is the largest genotype and phenotype series on FRDA in Indian population. This study showed GAA1 size affects the cerebellar atrophy, muscles twisting and tremor.

Paediatric genomics: diagnosing rare disease in children

Caroline F. Wright, David R. FitzPatrick & Helen V. Firth, Nature Reviews Genetics, Published online:05 February 2018, doi:10.1038/nrg.2017.116

The majority of rare diseases affect children, most of whom have an underlying genetic cause for their condition. However, making a molecular diagnosis with current technologies and knowledge is often still a challenge. Paediatric genomics is an immature but rapidly evolving field that tackles this issue by incorporating next-generation sequencing technologies, especially whole-exome sequencing and whole-genome sequencing, into research and clinical workflows. This complex multidisciplinary approach, coupled with the increasing availability of population genetic variation data, has already resulted in an increased discovery rate of causative genes and in improved diagnosis of rare paediatric disease. Importantly, for affected families, a better understanding of the genetic basis of rare disease translates to more accurate prognosis, management, surveillance and genetic advice; stimulates research into new therapies; andenables provision of better support.

Ethical, legal and social implications of paediatric genomics:
Paediatric genomics has many of the same ethical, legal and social issues that clinical genetics has been dealing with for decades, such as reproductive autonomy, informed consent for research, misattributed parentage and implications for family members. Issues which are more complicated for paediatric testing: the reduced capacity of the child to consent to testing and/or research means that parents and clinicians have an increased role in deciding what may be in the best interests of the child. Most of the novel ethical issues in the era of genomics relate to the storage, interpretation and access of data.


Data storage: it is not clear who should have access to that data and when they should be allowed access to it. Should access be limited to clinicians involved in the direct care of the family or opened to researchers in industry and/or academia?
Confidentiality versus data access: Parents are often asked to make decisions about their child’s data that may have irreversible repercussions. Should these decisions be revisited when the child approaches and passes the age of majority?
Duty of care: For clinicians, the issue of data access is linked to the question of whether their duty of care is limited to finding a diagnosis for the child’s immediate problems or whether it extends beyond the scope of the initial investigation. The duty of care could also extend to looking for incidental predispositions to adult-onset conditions or to adverse drug reactions either in the child or their parents. In general, investigating children for adult-onset conditions for which there is no early treatment is not recommended.

Tandem repeats mediating genetic plasticity in health and disease

Anthony J. Hannan, Nature Reviews Genetics, Published online: 05 February 2018, doi:10.1038/nrg.2017.115

Accumulating evidence suggests that many classes of DNA repeats exhibit attributes that distinguish them from other genetic variants, including the fact that they are more liable to mutation; this enables them to mediate genetic plasticity. The expansion of tandem repeats, particularly of short tandem repeats, can cause a range of disorders (including Huntington disease, various ataxias, motor neuron disease, frontotemporal dementia, fragile X syndrome and other neurological disorders), and emerging data suggest that tandem repeat polymorphisms (TRPs) can also regulate gene expression in healthy individuals. TRPs in human genomes may also contribute to the missing heritability of polygenic disorders. A better understanding of tandem repeats and their associated repeatome, as well as their capacity for genetic plasticity via both germline and somatic mutations, is needed to transform our understanding of the role of TRPs in health and disease.

Sunday, February 4, 2018

Serum uric acid in Friedreich Ataxia

Tommaso Schirinzi, Gessica Vasco, Ginevra Zanni, Sara Petrillo, Fiorella Piemonte, Enrico Castelli, Enrico Silvio Bertini, Clinical Biochemistry, Available online 2 February 2018, ISSN 0009-9120, doi:10.1016/j.clinbiochem.2018.01.022.

Serum UA levels resulted significantly higher in FRDA than CTL, independently from age, gender and BMI. At the cut-off value of 4.45 mg/dl, serum UA discriminates FRDA from CTL with >70% of sensitivity and >60% of specificity. No correlations emerged with clinical data. Contrarily to other neurodegenerative diseases, in FRDA, we observed an independent increase of serum UA content. Taking in account previous experimental findings, we speculate that such a finding may result from biochemical impairment induced by the genetic defect, acting as a sort of compensatory antioxidant defense although proper dedicated studies are mandatory. This preliminary report focuses UA as a potential biomarker for FRDA and encourages further studies on novel therapeutic strategies.

Differential gene expression analysis reveals pathway based functional association of dysregulated genes in Friedreich’s ataxia

H.N. Singh, V. Swarup, A.K. Srivastava, Parkinsonism & Related Disorders, Volume 46, Supplement 2, January 2018, Page e34, ISSN 1353-8020,  doi:10.1016/j.parkreldis.2017.11.112.

A total of 3594 different gene-sets were identified and analyzed in the expression analysis. Out of 3594 gene-sets, 2009 were up-regulated in
the control phenotype and 1585 genes were up-regulated in FRDA conditions.


Sequence-specific DNA Binding Pyrrole–Imidazole Polyamides and Their Applications

Yusuke Kawamoto, Toshikazu Bando, Hiroshi Sugiyama, Bioorganic & Medicinal Chemistry, Available online 1 February 2018, ISSN 0968-0896, doi:10.1016/j.bmc.2018.01.026.

Pyrrole–imidazole polyamides (Py–Im polyamides) are cell-permeable compounds that bind to the minor groove of double-stranded DNA in a sequence-specific manner without causing denaturation of the DNA. These compounds can be used to control gene expression and to stain specific sequences in cells. Here, we review the history, structural variations, and functional investigations of Py–Im polyamides.


Prevalence of hemochromatosis (HFE) gene mutations in Friedreich’s Ataxia patients and peripheral neuropathy

I. Singh, S. Shakya, R.K. Singh, V. Goyal, A.K. Srivastava, Parkinsonism & Related Disorders, Volume 46, Supplement 2, January 2018, Page e4, ISSN 1353-8020, doi:10.1016/j.parkreldis.2017.11.014.

Allele frequency of p.H63D mutation was statistically higher (p-value 0.04) in cases than controls. Peripheral neuropathy in our patients
correlated with p.H63D (p-value 0.038)

Friday, February 2, 2018

A Genome-Wide Association Study Finds Genetic Associations with Broadly-Defined Headache in UK Biobank (N = 223,773)

Weihua Meng, Mark J. Adams, Harry L. Hebert, Ian J. Deary, Andrew M. McIntosh, Blair H. Smith, EBioMedicine, Available online 31 January 2018, ISSN 2352-3964, doi:10.1016/j.ebiom.2018.01.023.

Loci associated with broadly-defined headache: Gene FXN, Chromosome 9, Lead SNP rs4596713, P 2.30 × 10− 8, Effective allele T, Minor allele frequency 0.41, Beta− 0.0078, standard error 0.0014.

Neurology Measures in FA Children

February 1, 2018. ClinicalTrials.gov identifier (NCT number): NCT03418740


The purpose of this study is to identify ways to follow progression of Friedreich's Ataxia (FA) and be able to measure changes over time in children with FA. Participants will have biannual visits to observe how the disease progresses over time and determine the rate of progression.