Variations of frataxin protein levels in normal individuals.

Abstract

Friedreich's ataxia (FRDA) is the most common of the inherited ataxias and is associated with GAA trinucleotide repeat expansions within the first intron of the frataxin (FXN) gene. There are expanded FXN alleles from 66 to 1,700 GAA.TTC repeats in FRDA patients and correlations between number of GAA repeats and frataxin protein levels are assumed. Here, we present for the first time frataxin protein levels as well as analysis of GAA triplet repeats in the FXN gene in a population of 50 healthy Austrian people. Frataxin protein levels were measured in lymphocytes from blood samples by ELISA and GAA repeats were analyzed by capillary electrophoresis. Rather unexpectedly, we found a high variation of frataxin protein levels among the individuals. In addition, there was no correlation between frataxin levels, GAA repeats, age and sex in this group. However, these findings are of great importance for better characterization of the disease.

---

http://www.institut-de-france.fr/grands-prix-2010/communiques/del_duca_scientifique_anglais.pdf

 

Paris, May 2010
SIMONE AND CINO DEL DUCA FOUNDATION

The Grand Prix scientifique 2010
of the Simone and Cino del Duca Foundation was awarded to
Prof. PATRICK AUBOURG
Director of Inserm 745 Unit “Genetics and biotherapies of degenerative and proliferative diseases of
the nervous system” - Saint-Vincent de Paul Hospital, Paris
The Grand Prix scientifique of the Simone and Cino del Duca Foundation, worth 300,000 euros, aims to reward either a French or foreign research team. The 2010 Prix theme was “Vectorization of bioactive molecules for the treatment of severe pathologies”.
The Jury, composed of eminent scientists, most of whom members of the Académie des
sciences, awarded the 2010 Prix to Prof. Patrick Aubourg and his team, to reward their critical findings in the field of genetic diseases of the central nervous system.

 

The Therapeutic Mode of Action of 4-Aminopyridine in Cerebellar Ataxia

Karina Alviña and Kamran Khodakhah

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to Kamran Khodakhah, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Kennedy Center, Room 506, 1410 Pelham Parkway South, Bronx, New York 10461. Email: k.khodakhah@einstein.yu.edu

Episodic ataxia type 2 (EA2) is a hereditary cerebellar ataxia associated with mutations in the P/Q-type voltage-gated calcium (Ca2+) channels. Therapeutic approaches for treatment of EA2 are very limited. Presently, the potassium (K+) channel blocker 4-aminopyridine (4-AP) constitutes the most promising treatment, although its mechanism of action is not understood. Here we show that, in contrast to what is commonly believed, therapeutic concentrations of 4-AP do not increase the inhibitory drive of cerebellar Purkinje cells. Instead, 4-AP restores the severely diminished precision of pacemaking in Purkinje cells of EA2 mutant mice by prolonging the action potential and increasing the action potential afterhyperpolarization. Consistent with this mode of action, the therapeutic efficacy of 4-AP was comparable, and not additive, to chlorzoxazone, an activator of Ca2+-dependent K+ channels that also restores the precision of Purkinje cell pacemaking. The likely target of 4-AP at the concentrations used are the Kv1 family of K+ channels, possibly the Kv1.5 subtype. Because at higher concentrations 4-AP blocks a large array of K+ channels and is a proconvulsant, use of selective Kv1 channel blockers is likely to be a safer substitute for treatment of cerebellar ataxia.
--------------------------------------------------------------------------------
Received July 23, 2009; revised March 17, 2010; accepted April 8, 2010.

Correspondence should be addressed to Kamran Khodakhah, Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Kennedy Center, Room 506, 1410 Pelham Parkway South, Bronx, New York 10461. Email: k.khodakhah@einstein.yu.edu
 

---

http://www.jneurosci.org/cgi/content/short/30/21/7249?rss=1

KCa Channels as Therapeutic Targets in Episodic Ataxia Type-2

Karina Alviña1,2 and Kamran Khodakhah1

1Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461, and 2Departmento de Ciencias Fisiológicas, Pontificia Universidad Católica de Chile, Santiago, 8331150, Chile

Correspondence should be addressed to Kamran Khodakhah, Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center, Room 506, Bronx, NY 10461. Email: K.Khodakhah@einstein.yu.edu

Episodic ataxia type-2 (EA2) is an inherited movement disorder caused by mutations in the gene encoding the Cav2.11 subunit of the P/Q-type voltage-gated calcium channel that result in an overall reduction in the P/Q-type calcium current. A consequence of these mutations is loss of precision of pacemaking in cerebellar Purkinje cells. This diminished precision reduces the information encoded by Purkinje cells and is thought to contribute to symptoms associated with this disorder. The loss of the precision of pacemaking in EA2 is the consequence of reduced activation of calcium-dependent potassium channels (KCa) by the smaller calcium current and in vitro can be pharmacologically restored by KCa activators. We used a well established mouse model of EA2, the tottering (tg/tg) mouse, to examine the potential therapeutic utility of one such Food and Drug Administration (FDA)-approved compound, chlorzoxazone (CHZ). Compared with wild-type Purkinje cells, we found the firing rate of tg/tg Purkinje cells in acutely prepared cerebellar slices to be very irregular. Bath application of CHZ successfully restored the precision of pacemaking in a dose-dependent manner. Oral administration of CHZ to tg/tg mice improved their baseline motor performance and reduced the severity, frequency, and duration of episodes of dyskinesia without producing any adverse effects. We propose the use of CHZ, which is currently FDA approved as a muscle relaxant, as a safe and novel treatment of EA2.
 

--------------------------------------------------------------------------------
Received Dec. 22, 2009; revised March 16, 2010; accepted April 5, 2010.

Correspondence should be addressed to Kamran Khodakhah, Department of Neuroscience, Albert Einstein College of Medicine, 1410 Pelham Parkway South, Kennedy Center, Room 506, Bronx, NY 10461. Email: K.Khodakhah@einstein.yu.edu
 

---

http://www.prnewswire.com/news-releases/repligen-receives-orphan-drug-designation-from-the-fda-for-rg2833-for-friedreichs-ataxia-94737209.html

About Repligen Corporation

Repligen Corporation is a biopharmaceutical company focused on the development of novel therapeutics for neurological disorders.  In addition, we are the world's leading supplier of recombinant Protein A, the sales of which partially fund the advancement of our development pipeline while supporting our financial stability.  Repligen's corporate headquarters are located at 41 Seyon Street, Building #1, Suite 100, Waltham, MA 02453.  Additional information may be requested from www.repligen.com.

This press release contains forward-looking statements which are made pursuant to the safe harbor provisions of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended. The forward-looking statements in this release do not constitute guarantees of future performance. Investors are cautioned that statements in this press release which are not strictly historical statements, including, without limitation, statements regarding current or future financial performance and position, management's strategy, plans and objectives for future operations, plans and objectives for product development, plans and objectives for present and future clinical trials and results of such trials, plans and objectives for regulatory approval, litigation, intellectual property, product development, manufacturing plans and performance such as the anticipated growth in the monoclonal antibody market and our other target markets and projected growth in product sales, constitute forward-looking statements. Such forwardlooking statements are subject to a number of risks and uncertainties that could cause actual results to differ materially from those anticipated, including, without limitation, risks associated with: the success of current and future collaborative relationships, the market acceptance of our products, our ability to compete with larger, better financed pharmaceutical and biotechnology companies, new approaches to the treatment of our targeted diseases, our expectation of incurring continued losses, our uncertainty of product revenues and profits, our ability to generate future revenues, our ability to raise additional capital to continue our drug development programs, the success of our clinical trials, our ability to develop and commercialize products, our ability to obtain required regulatory approvals, our compliance with all Food and Drug Administration regulations, our ability to obtain, maintain and protect intellectual property rights for our products, the risk of litigation regarding our intellectual property rights, our limited sales and manufacturing capabilities, our dependence on third-party manufacturers and value added resellers, our ability to hire and retain skilled personnel, our volatile stock price, and other risks detailed in Repligen's filings with the Securities and Exchange Commission. Repligen assumes no obligation to update any forward-looking information contained in this press release or with respect to the announcements described herein.

---

http://www.ncbi.nlm.nih.gov/pubmed/20478553?dopt=Abstract


Am J Obstet Gynecol. 2010 May 15.

Pregnancy with Friedreich ataxia: a retrospective review of medical risks and psychosocial implications.
Friedman LS, Paulsen EK, Schadt KA, Brigatti KW, Driscoll DA, Farmer JM, Lynch DR.

Departments of Neurology and Pediatrics, University of Pennsylvania School of Medicine, and Children's Hospital of Philadelphia.

Abstract
OBJECTIVE: Friedreich ataxia (FRDA) is an autosomal recessive, neurodegenerative disease. Recent medical advances have improved the average life expectancy, and as such, many female patients are contemplating pregnancy. However, little research exists exploring the medical or psychosocial complications that arise from pregnancy with this disease. STUDY DESIGN: In this study, we retrospectively examined 31 women with FRDA who had 65 pregnancies, resulting in 56 live offspring. RESULTS: FRDA did not appear to increase the risk of spontaneous abortion, preeclampsia, or preterm birth. Despite the sensory and proprioceptive loss that occurs in FRDA, nearly four fifths of births were vaginal. Of babies, 94.4% were discharged home with their mothers. Equal numbers of women reported that pregnancy made their disease symptoms worse, better, or unchanged. CONCLUSION: This study demonstrates that women with FRDA can have uncomplicated pregnancies that do not uniformly complicate disease symptomatology. Copyright © 2010 Mosby, Inc. All rights reserved.

---

Analysis of the factors influencing the cardiac phenotype in Friedreich's ataxia.
Rajagopalan B, Francis JM, Cooke F, Korlipara LV, Blamire AM, Schapira AH, Madan J, Neubauer S, Cooper JM.

Nuffield Department of Medicine, Department of Biochemistry, University of Oxford, Oxford, UK.

Abstract
Friedreich's ataxia (FRDA) has been associated with both cardiac hypertrophy and to a lesser degree dilated cardiomyopathy. We have conducted a cross sectional magnetic resonance imaging (MRI) study of 25 patients with clinically and genetically confirmed FRDA and 24 healthy controls to analyse how disease parameters influence cardiac features in FRDA. MR cine imaging in the long and short axis planes was performed alongside clinical assessments. LV mass was most pronounced in FRDA patients with a larger genetic mutation (GAA1 repeats >600), earlier age of onset (<16years) and a shorter disease duration (<15 years). LV mass decreased with longer disease duration (>15 years), and independent of GAA1 repeat size and age of onset, suggesting cardiac thinning occurred with prolonged disease. Heart function was lower in patients with larger GAA1 repeat number and longer disease duration. Consequently, cardiac hypertrophy was more marked in FRDA patients with a larger GAA1 repeat number and younger age of onset, while prolonged disease duration was associated with lower LV mass and decreased heart function. It is important not only to understand the biochemical basis for these cardiac changes but also allow for these changes when assessing the effect of treatment of FRDA patients. (c) 2010 Movement Disorder Society.

---

J Neurol Neurosurg Psychiatry. 2010 May;81(5):529-32.
The wide clinical spectrum and nigrostriatal dopaminergic damage in spinocerebellar ataxia type 6.
Kim JM, Lee JY, Kim HJ, Kim JS, Kim YK, Park SS, Kim SE, Jeon BS.
Seoul National University Hospital, Department of Neurology, Chongno-Ku Yunkeun-Dong 28, Seoul 110-744, South Korea.
Abstract
Spinocerebellar ataxia type 6 (SCA6) manifests a wide spectrum of non-cerebellar system involvements. The objective of this study was to examine the presence of nigrostriatal dopaminergic system derangement in SCA6. Eight patients with SCA6 who underwent a regular follow-up for at least 2 years participated in this study. A detailed neurological examination was performed and striatal dopamine transporter (DAT) was evaluated using [(99m)Tc]-TRODAT-1 SPECT. The main clinical feature of SCA6 was cerebellar ataxia with impaired eye movements. However, a wide spectrum of non-cerebellar system involvements, such as autonomic dysfunction, and pyramidal and extrapyramidal signs, was also observed. Two patients had bradykinesia. l-dopa was tried in one patient without benefit. Of the two patients with bradykinesia, DAT density was reduced to the Parkinson's disease (PD) range with a rostrocaudal gradient typical of PD in one patient (CAG repeats 13/22) and was mildly decreased in the other patient (12/25). Of the four patients without extrapyramidal signs, three (12/22, 11/25, 17/22) showed mild to severe reduction of DAT density and one (13/22) had a normal density. This study shows that SCA6 has a varying degree of nigro striatal dopaminergic derangement. Two patients manifested mild bradykinesia, emphasising the need to screen for SCA6, even in patients with progressive ataxia and parkinsonism. Further histopathological studies would be helpful to determine the nigrostriatal dopaminergic damage in SCA6

---

http://www.ncbi.nlm.nih.gov/pubmed/20464573?dopt=Abstract

Ataxia with vitamin E deficiency: update of molecular diagnosis.
Di Donato I, Bianchi S, Federico A.

Dipartimento di Scienze Neurologiche, Neurochirurgiche e del Comportamento, Università degli Studi di Siena, Viale Bracci, 53100, Siena, Italy.

Abstract
Ataxia with vitamin E deficiency (AVED) is a rare autosomal recessive neurodegenerative disease, due to mutations in TTPA gene (Arita et al. in Biochem J 306(Pt. 2):437-443, 1995; Hentati et al. in Ann Neurol 39:295-300, 1996), which encodes for alpha-TTP, a cytosolic liver protein that is presumed to function in the intracellular transport of alpha-tocopherol. This disease is characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. The neurological symptoms include ataxia, dysarthria, hyporeflexia, and decreased vibration sense, sometimes associated with cardiomyopathy and retinitis pigmentosa (Mariotti et al. in Neurol Sci 25:130-137, 2004). Vitamin E supplementation improves symptoms and prevents disease progress (Doria-Lamba et al. in Eur J Pediatr 165(7):494-495, 2006). Over 20 mutations have been identified in patients with AVED. In the present paper we summarize the recent findings on molecular genetic of this disease including the list of the known mutations.

---

http://www.prnewswire.com/news-releases/repligen-files-investigational-new-drug-application-with-fda-for-first-drug-targeting-the-core-genetic-defect-of-friedreichs-ataxia-93666409.html
 

Friedreich's ataxia is an inherited neurodegenerative disease caused by a defect in a single gene that results in inadequate production of the protein frataxin.  Low levels of frataxin lead to degeneration of both the nerves controlling muscle movements in the arms and legs and the nerve tissue in the spinal cord.  Preclinical studies in animal models and patients' cells have shown that RG2833 crosses the blood brain barrier, activates the defective frataxin gene and increases production of the protein frataxin.  These results indicate that RG2833 may increase frataxin production and arrest disease progression in patients with Friedreich's ataxia.

RG2833 is a new chemical entity which is the subject of a composition of matter patent application which if allowed, will remain in force until 2029 prior to any patent term extensions.  Repligen is also evaluating HDAC-3 inhibitors in animal models of Huntington's disease and cognition.  RG2833 has been developed in collaboration with scientists from The Scripps Research Institute and a broad network of international scientific thought leaders.  Repligen's research efforts have been partially funded with grants from the Muscular Dystrophy Association, the Friedreich's Ataxia Research Alliance, GoFAR and the National Ataxia Foundation.

---

http://journals.lww.com/geneticsinmedicine/Fulltext/2010/04001/Spinocerebellar_ataxia__Patient_and_health.7.aspx#P11
 

Spinocerebellar ataxia: Patient and health professional perspectives on whether and how patents affect access to clinical genetic testing
Powell, Ashton PhD; Chandrasekharan, Subhashini PhD; Cook-Deegan, Robert MD

Author InformationFrom the 1Center for Public Genomics, Center for Genome Ethics, Law and Policy, Institute of Genome Sciences and Policy, Duke University, Curriculum in Neurobiology, University of North at Carolina Chapel Hill, Center for Genomics and Society at the University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; and 2Center for Genome Ethics, Law and Policy, Institute for Genome Sciences and Policy, Duke University, Durham, North Carolina.

Robert Cook-Deegan, MD, Center for Genome Ethics, Law and Policy, Institute for Genome Sciences and Policy, Duke University, Box 90141, Durham, NC 27708. E-mail: gelp@duke.edu.

Disclosure: The authors declare no conflict of interest. See Acknowledgments for details.

AbstractGenetic testing for spinocerebellar ataxia is used in diagnosis of rare movement disorders. Such testing generally does not affect treatment, but confirmation of mutations in a known gene can confirm diagnosis and end an often years-long quest for the cause of distressing and disabling symptoms. Through interviews and a web forum hosted by the National Ataxia Foundation, patients and health professionals related their experiences with the effect of patents on access to genetic testing for spinocerebellar ataxia. In the United States, Athena Diagnostics holds either a patent or an exclusive license to a patent in the case of six spinocerebellar ataxia variants (spinocerebellar ataxia 1–3 and 6–8) and two other hereditary ataxias (Friedreich's Ataxia and Early Onset Ataxia). Athena has enforced its exclusive rights to spinocerebellar ataxia-related patents by sending notification letters to multiple laboratories offering genetic testing for inherited neurological conditions, including spinocerebellar ataxia. Roughly half of web forum respondents had decided not to get genetic tests. Price, coverage and reimbursement by insurers and health plans, and fear of genetic discrimination were the main reasons cited for deciding not to get tested. Price was cited as an access concern by the physicians, and as sole US provider, coverage and reimbursement depend on having payment agreements between Athena and payers. In cases in which payers do not reimburse, the patient is responsible for payment, although some patients can apply to the voluntary Athena Access and Patient Protection Plan offered by the company

---

http://www3.interscience.wiley.com/journal/123393744/abstract?CRETRY=1&SRETRY=0

BRIEF COMMUNICATION
Carbamylated erythropoietin increases frataxin independent from the erythropoietin receptor
Brigitte Sturm*, Melissa Helminger*, Hannes Steinkellner*, Mohammad Mehdi Heidari*,†, Hans Goldenberg* and Barbara Scheiber-Mojdehkar*
*Medical University of Vienna, Vienna, Austria , † Yazd University, Yazd, Iran
Correspondence to Barbara Scheiber-Mojdehkar, Department of Medical Chemistry, Medical University of Vienna, Waehringerstr 10, A-1090 Vienna, Austria. Tel.: 43-1-4277/60891; fax: 43-1-4277/60881; e-mail: barbara.scheiber-mojdehkar@meduniwien.ac.at
Copyright Journal Compilation © 2010 Stichting European Society for Clinical Investigation Journal Foundation
KEYWORDS
Carbamylated erythropoietin • erythropoietin receptor • frataxin • Friedreich's ataxia • nonerythropoietic erythropoietin • recombinant human erythropoietin
Eur J Clin Invest 2010; 40 (6): 561–565

ABSTRACT
Background Friedreich's ataxia (FRDA) is a neurodegenerative disorder caused by decreased expression of the mitochondrial protein frataxin. Recently we showed in a clinical pilot study in Friedreich's ataxia patients that recombinant human erythropoietin (rhuEPO) significantly increases frataxin-expression. In this in vitro study, we investigated the role of the erythropoietin receptor (EPO-R) in the frataxin increasing effect of rhuEPO and if nonerythropoietic carbamylated erythropoietin (CEPO), which cannot bind to the classical EPO-R increases frataxin expression.

Materials and methods In our experiments human erythroleukaemic K562 cells (+ EPO-R), human monocytic leukemia THP-1 cells (− EPO-R) and isolated primary lymphocytes from healthy control and FRDA patients were incubated with different concentrations of rhuEPO or CEPO. Frataxin-expression was detected by an electrochemical luminescence immunoassay (based on the principle of an ELISA).

Results We show that rhuEPO increases frataxin-expression in K562 cells (expressing EPO-R) as well as in THP-1 cells (without EPO-R expression). These results were confirmed by the finding that CEPO, which cannot bind to the classical EPO-R increased frataxin expression in the same concentration range as rhuEPO. In addition, we show that both EPO derivatives significantly increase frataxin-expression in vitro in control and Friedreich's ataxia patients primary lymphocytes.

Conclusion Our results provide a scientific basis for further studies examining the effectiveness of nonerythropoietic derivatives of erythropoietin for the treatment of Friedreich's ataxia patients.