Peptide SS-31 upregulates frataxin expression and improves the quality of mitochondria: implications in the treatment of Friedreich ataxia
Hongting Zhao, Huihui Li, Shuangying Hao, Jiping Chen, Jing Wu, Chuanhui Song, Meng Zhang, Tong Qiao & Kuanyu Li
Friedreich ataxia is a progressive neurodegenerative disease caused by the expansion of GAA trinucleotide repeats within the first intron of the FXN gene, which encodes frataxin. The pathophysiology of the disease is thought to be derived from the decrease of Fe-S cluster biogenesis due to frataxin deficiency. There is currently no effective treatment for the disease. In our study, we demonstrated that treatment with the mitochondrion-targeted peptide SS-31 reduced frataxin deficiency-induced oxidative stress in lymphoblasts and fibroblasts derived from patients. Interestingly, SS-31 treatment translationally upregulated the protein level of frataxin in a dose-dependent manner. Furthermore, SS-31 treatment increased the enzymatic activities of the iron-sulphur enzymes, including aconitase and complex II and III of the respiratory chain. Further evaluation of the quality of mitochondria showed that mitochondrial membrane potential, ATP content, NAD+/NADH, and the morphology of mitochondria all improved. Our results suggest that SS-31 might potentially be a new drug for the early treatment of Friedreich ataxia
[Advances in Neurological Therapeutics for Friedreich Ataxia and Machado-Joseph Disease].
[Article in Japanese]
We reviewed advances in therapeutics for both Friedreich ataxia and Machado-Joseph disease. Various clinical trials have been carried out, mainly for Friedreich ataxia; however, the therapeutic reports from these trials have not provided much evidence for success. Some interesting clinical trials have been reported, and further developments are expected. Regenerative therapy using umbilical cord mesenchymal stem cells and a therapeutic study investigating a new pathomechanism in animal and/or cell culture studies were reported. We expect that these results will translate to therapeutic strategies for patients with these disorders. In addition, biomarkers play an important role when novel treatments are discovered and clinical trials are performed: hence at present, a number of biomarkers such as gait analysis by triaxial accelerometers and prism adaptation of hand-reaching movements, are being examined.
Cerebral Abnormalities in Friedreich Ataxia: A Review
Friedreich ataxia (FRDA) is an inherited degenerative disorder affecting multiple systems of the body and resulting in symptoms which include progressive ataxia, dysarthria, and cardiomyopathy. Central nervous system pathology has been traditionally ascribed to the spinal cord and dentate nucleus of the cerebellum. However, cerebral abnormalities in FRDA are being increasingly documented via multiple neuroimaging techniques. Understanding the nature and implications of cerebral abnormalities in FRDA provides more comprehensive knowledge of nervous system involvement in this disorder and increases the prospects of identifying effective treatment targets. We review the cerebellar and the cerebral involvement with a focus on the emerging in vivo human neuroimaging findings suggesting wide-spread cerebral involvement, including aberrant cerebellar-cerebral connectivity. We synthesise the findings by proposing potential mechanisms that may drive these effects. Finally, we identify future research directions which, we argue, will lead to a better understanding of the extent and potential mechanisms of cerebral aberrations in FRDA.
Mechanisms of unexpected death and autopsy findings in Friedreich ataxia
A 36-year-old woman with a clinical history of Friedreich ataxia and hypertrophic cardiomyopathy was found unexpectedly dead at her home. The heart showed asymmetric left ventricular hypertrophy, with an interventricular septal thickness of 20–25 mm (the remainder of the left ventricular wall measured 15 mm). Histologically, both ventricles had irregular areas of marked myocyte hypertrophy with associated interstitial fibrosis and focal myofibre disarray. There was neuronal loss within the dentate nucleus of the cerebellum, with vacuolation and axonal loss in the dorsal columns and spinocerebellar tracts of the upper cervical spinal cord. Death was due to hypertrophic cardiomyopathy complicating Friedreich ataxia. Other causes of death in this condition include embolic stroke, cerebral haemorrhage, aspiration pneumonia, renal failure, diabetic ketoacidosis, myocardial infarction, generalised inanition and trauma. Sudden death due to cardiac disease, resulting in presentation for medicolegal autopsy, may be the presenting feature at all ages, including childhood.
Mitochondrial biogenesis and neural differentiation of human iPSC is modulated by idebenone in a developmental stage-dependent manner
- P. Stepien
Idebenone, the synthetic analog of coenzyme Q10 can improve electron transport in mitochondria. Therefore, it is used in the treatment of Alzheimer’s disease and other cognitive impairments. However, the mechanism of its action on neurodevelopment is still to be elucidated. Here we demonstrate that the cellular response of human induced pluripotent stem cells (hiPSC) to idebenone depends on the stage of neural differentiation. When: neural stem cells (NSC), early neural progenitors (eNP) and advanced neural progenitors (NP) have been studied a significant stimulation of mitochondrial biogenesis was observed only at the eNP stage of development. This coexists with the enhancement of cell viability and increase in total cell number. In addition, we report novel idebenone properties in a possible regulation of neural stem cells fate decision: only eNP stage responded with up-regulation of both neuronal (MAP2), astrocytic (GFAP) markers, while at NSC and NP stages significant down-regulation of MAP2 expression was observed, promoting astrocyte differentiation. Thus, idebenone targets specific stages of hiPSC differentiation and may influence the neural stem cell fate decision.
Reversible axonal dystrophy by calcium modulation in frataxin-deficient sensory neurons of YG8R mice.
Belén Mollá1, 2, Diana C. Muñoz-Lasso1, 3, 4, Fatima Riveiro1, 5, Arantxa Bolinches-Amorós1, 6, Federico V. Pallardó1, 3, 4, Angel Fernandez-Vilata7, Maria D. Vaya6, 7, 8,Francesc Palau1, 9, 10 and Pilar Gonzalez-Cabo1, 3, 4*
- 1Centre for Biomedical Network Research on Rare Diseases, Spain
- 2Biomedical Institute of Valencia (CSIC), Spain
- 3Department of Physiology, Universitat de València, Spain
- 4Associated Unit for rare diseases INCLIVA-CIPF, Spain
- 5Hospital Clínico Universitario, Fundación Pública Galega de Medicina Xenómica, Spain
- 6Centro de Investigacion Principe Felipe, Spain
- 7Health Regional Ministry of Valencia (CEIB-CS), Centre of Excellence in Technological Innovation in Bioimaging, Spain
- 8Centro de Investigación Biomédica en Red de Salud Mental, Spain
- 9Department of Genetic & Molecular Medicine and IPER, Hospital Sant Joan de Déu Barcelona, Spain
- 10Department of Pediatrics, University of Barcelona, Spain
Friedreich’s ataxia (FRDA) is a peripheral neuropathy involving a loss of proprioceptive sensory neurons. Studies of biopsies from patients suggest that axonal dysfunction precedes the death of proprioceptive neurons in a dying-back process. We observed that the deficiency of frataxin in sensory neurons of dorsal root ganglia (DRG) of the YG8R mouse model causes the formation of axonal spheroids which retain dysfunctional mitochondria, shows alterations in the cytoskeleton and it produces impairment of axonal transport and autophagic flux. The homogenous distribution of axonal spheroids along the neurites supports the existence of continues focal damages. This lead us to propose for FRDA a model of distal axonopathy based on axonal focal damages. In addition, we observed the involvement of oxidative stress and dyshomeostasis of calcium in axonal spheroid formation generating axonal injury as a primary cause of pathophysiology. Axonal spheroids may be a consequence of calcium imbalance, thus we propose the quenching or removal extracellular Ca2+ to prevent spheroids formation. In our neuronal model, treatments with BAPTA and o-phenanthroline reverted the axonal dystrophy and the mitochondrial dysmorphic parameters. These results support the hypothesis that axonal pathology is reversible in FRDA by pharmacological manipulation of intracellular Ca2+ with Ca2+ chelators or metalloprotease inhibitors, preventing Ca2+-mediated axonal injury. Thus, the modulation of Ca2+ levels may be a relevant therapeutic target to develop early axonal protection and prevent dying-back neurodegeneration.
Heart and Nervous System Pathology in Compound Heterozygous Friedreich Ataxia
Alyssa B. Becker, BA Jiang Qian, MD, PhD Benjamin B. Gelman, MD, PhDMichele Yang, MD Peter Bauer, MD Arnulf H. Koeppen, MD
In a small percentage of patients with Friedreich ataxia (FA), the pathogenic mutation is compound heterozygous, consisting of a guanine–adenine–adenine (GAA) trinucleotide repeat expansion in one allele, and a deletion, point mutation, or insertion in the other. In 2 cases of compound heterozygous FA, the GAA expansion was inherited from the mother, and deletions from the father. Compound heterozygous FA patient 1, an 11-year-old boy (GAA, 896/c.11_12TCdel), had ataxia, chorea, cardiomyopathy, and diabetes mellitus. Compound heterozygous FA patient 2, a 28-year-old man (GAA, 744/exon 5 del), had ataxia, cardiomyopathy, and diabetes mellitus. Microscopy showed cardiomyocyte hypertrophy, iron-positive inclusions, and disrupted intercalated discs. The cardiac lesions were similar to those in age-matched homozygous FA patients with cardiomyopathy and diabetes mellitus (boy, 10, GAA 1016/1016; woman, 25, GAA 800/1100). The neuropathology was also similar and included hypoplasia of spinal cord and dorsal root ganglia, loss of large axons in dorsal roots, and atrophy of the dentate nucleus (DN). Frataxin levels in heart and DN of all 4 FA cases were at or below the detection limits of the enzyme-linked immunosorbent assay (≤10 ng/g wet weight) (normal DN: 126 ± 43 ng/g; normal heart: 266 ± 92 ng/g). The pathologic phenotype in homozygous and compound heterozygous FA is determined by residual frataxin levels rather than unique mutations.
Mitochondrial dysfunction in the neuro-degenerative and cardio-degenerative disease, Friedreich’s ataxia
Mitochondrial homeostasis is essential for maintaining healthy cellular function and survival. The detrimental involvement of mitochondrial dysfunction in neuro-degenerative diseases has recently been highlighted in human conditions, such as Parkinson’s, Alzheimer’s and Huntington’s disease. Friedreich’s ataxia (FA) is another neuro-degenerative, but also cardio-degenerative condition, where mitochondrial dysfunction plays a crucial role in disease progression. Deficient expression of the mitochondrial protein, frataxin, is the primary cause of FA, which leads to adverse alterations in whole cell and mitochondrial iron metabolism. Dys-regulation of iron metabolism in these compartments, results in the accumulation of inorganic iron deposits in the mitochondrial matrix that is thought to potentiate oxidative damage observed in FA. Therefore, the maintenance of mitochondrial homeostasis is crucial in the progression of neuro-degenerative conditions, particularly in FA. In this review, vital mitochondrial homeostatic processes and their roles in FA pathogenesis will be discussed. These include mitochondrial iron processing, mitochondrial dynamics (fusion and fission processes), mitophagy, mitochondrial biogenesis, mitochondrial energy production and calcium metabolism.
Impact of diabetes in the Friedreich ataxia clinical outcome measures study
- Ashley McCormick1,
- Jennifer Farmer1,2,3,
- Susan Perlman4,
- Martin Delatycki5,
- George Wilmot6,
- Katherine Matthews7,
- Grace Yoon8,
- Chad Hoyle9,
- Sub H. Subramony10,
- Theresa Zesiewicz11,
- David R. Lynch1,2,3and
- Shana E. McCormack3,12,*
Friedreich ataxia (FA) is a progressive neuromuscular disorder caused by GAA triplet repeat expansions or point mutations in the FXN gene. FA is associated with increased risk of diabetes mellitus (DM). This study assessed the age-specific prevalence of FA-associated DM and its impact on neurologic outcomes.
Research Design and Methods
Participants were 811 individuals with FA from 12 international sites in a prospective natural history study (FA Clinical Outcome Measures Study, FACOMS). Physical function was assessed, using validated instruments. Multivariable regression analyses examined the independent association of DM with outcomes.
Mean age of participants was 30.1 years (SD 15.3, range: 7–82), 50% were female, and 94% were non-Hispanic white. 9% (42/459) of adults and 3% (10/352) of children had DM. Individuals with FA-associated DM were older (P < 0.001), had longer GAA repeat length on the least affected FXN allele (P = 0.037), and more severe FA (P = 0.0001). Of individuals with DM, 65% (34/52) were taking insulin. Even after accounting statistically for both age and GAA repeat length, DM was independently associated with greater FA symptom burden (P = 0.010), reduced capacity to perform activities of daily living (P = 0.021), and a decrease of 0.33 SDs on a composite performance measure (95% CI: −0.56–0.11, P = 0.004); the relative impact of DM was most apparent in younger individuals.
DM-associated FA has an independent adverse impact on well-being in affected individuals, particularly at younger ages. In future, evidence-based approaches for identification and management of FA-related DM may improve both health and function.
Pharmacological therapeutics in Friedreich ataxia: the present state
Introduction: Friedreich ataxia (FRDA) is a progressive, inherited, neurodegenerative disease for which there is currently no cure or approved treatment. FRDA is caused by deficits in the production and expression of frataxin, a protein found in the mitochondria that is most likely responsible for regulating iron-sulfur cluster enzymes within the cell. A decrease in frataxin causes dysfunction of adenosine triphosphate synthesis, accumulation of mitochondrial iron, and other events leading to downstream cellular dysfunction.
Areas covered: Therapeutic development for FRDA currently focuses on improving mitochondrial function and finding ways to increase frataxin expression. Additionally, the authors will review potential approaches aimed at iron modulation and genetic modulation. Finally, gene therapy is progressing rapidly and is being explored as a treatment for FRDA.
Expert commentary: The collection of multiple therapeutic approaches provides many possible ways to treat FRDA. Although the mitochondrial approaches are not thought to be curative, as the primary frataxin deficit will remain, they may still produce improvements in quality of life and slowing of progression. Therapies aimed at frataxin restoration are more likely to truly modify the disease, with gene therapy as the best possibility to alter the course of the disease from both a cardiac and neurological perspective.
Circulating miR-323-3p is a biomarker for cardiomyopathy and an indicator of phenotypic variability in Friedreich’s ataxia patients
- M. Seco-Cervera,
- D. González-Rodríguez,
- J. S. Ibáñez-Cabellos,
- L. Peiró-Chova,
- P. González-Cabo,
- E. García-López,
- J. J. Vílchez,
- I. Sanz-Gallego,
- F. V. Pallardó &
- J. L. García-Giménez
MicroRNAs (miRNAs) are noncoding RNAs that contribute to gene expression modulation by regulating important cellular pathways. In this study, we used small RNA sequencing to identify a series of circulating miRNAs in blood samples taken from Friedreich’s ataxia patients. We were thus able to develop a miRNA biomarker signature to differentiate Friedreich’s ataxia (FRDA) patients from healthy people. Most research on FDRA has focused on understanding the role of frataxin in the mitochondria, and a whole molecular view of pathological pathways underlying FRDA therefore remains to be elucidated. We found seven differentially expressed miRNAs, and we propose that these miRNAs represent key mechanisms in the modulation of several signalling pathways that regulate the physiopathology of FRDA. If this is the case, miRNAs can be used to characterize phenotypic variation in FRDA and stratify patients’ risk of cardiomyopathy. In this study, we identify miR-323-3p as a candidate marker for phenotypic differentiation in FRDA patients suffering from cardiomyopathy. We propose the use of dynamic miRNAs as biomarkers for phenotypic characterization and prognosis of FRDA.
How does performance of the Friedreich Ataxia Functional Composite compare to rating scales?
Progression of Friedreich ataxia (FRDA) is often measured using neurological rating scales such as the Friedreich Ataxia Rating Scale (FARS). Performance scales comprising functional measures have been used in other conditions due to their increased sensitivity and reproducibility and may replace examination-based measures. The aims of this study were to examine the relationship between the Friedreich Ataxia Functional Composite (FAFC) measures and characteristics of FRDA to determine if the FAFC is more sensitive to clinical change over time compared to its components. One hundred and twenty-two individuals completed the timed 25-foot walk (T25FW), 9-Hole Peg Test (9HPT) and the low-contrast letter acuity (LCLA) test at baseline, 63 at year 1, 34 at year 2 and 25 at year 3. Composite scores, Z2 (T25FW and 9HPT) and Z3 (T25FW, 9HPT and LCLA) were created. Correlation analyses were conducted. Change in FAFC components were examined over 1, 2, and 3 years. The FARS, Z2, Z3 and 9HPT showed significant change over all time points compared to baseline. The T25FW only demonstrated significant change over 3 years. The LCLA demonstrated no significant change over any of the time points. The FAFC shows significant change over time and indicates disease progression, however, this may result from individual components driving the differences. The LCLA showed no change over time, rendering Z3 redundant. The FAFC is of limited value in cohorts with non-ambulant individuals as it leads to skewing of the dataset and is better suited to less affected populations.
Selected missense mutations impair frataxin processing in Friedreich ataxia
- Elisia Clark1,2,
- Jill S. Butler3,
- Charles J. Isaacs2,
- Marek Napierala3and
- David R. Lynch1,2,*
Frataxin (FXN) is a highly conserved mitochondrial protein. Reduced FXN levels cause Friedreich ataxia, a recessive neurodegenerative disease. Typical patients carry GAA repeat expansions on both alleles, while a subgroup of patients carry a missense mutation on one allele and a GAA repeat expansion on the other. Here, we report that selected disease-related FXN missense mutations impair FXN localization, interaction with mitochondria processing peptidase, and processing.
Immunocytochemical studies and subcellular fractionation were performed to study FXN import into the mitochondria and examine the mechanism by which mutations impair FXN processing. Coimmunoprecipitation was performed to study the interaction between FXN and mitochondrial processing peptidase. A proteasome inhibitor was used to model traditional therapeutic strategies. In addition, clinical profiles of subjects with and without point mutations were compared in a large natural history study.
FXNI154F and FXNG130V missense mutations decrease FXN81–210 levels compared with FXNWT, FXNR165C, and FXNW155R, but do not block its association with mitochondria. FXNI154F and FXNG130V also impair FXN maturation and enhance the binding between FXN42–210 and mitochondria processing peptidase. Furthermore, blocking proteosomal degradation does not increase FXN81–210 levels. Additionally, impaired FXN processing also occurs in fibroblasts from patients with FXNG130V. Finally, clinical data from patients with FXNG130V and FXNI154F mutations demonstrates a lower severity compared with other individuals with Friedreich ataxia.
These data suggest that the effects on processing associated with FXNG130V and FXNI154F mutations lead to higher levels of partially processed FXN, which may contribute to the milder clinical phenotypes in these patients.
Cerebellar ataxia and intrathecal baclofen therapy: Focus on patients´ experiences
- Shala Ghaderi Berntsson ,
- Anne-Marie Landtblom,
- Gullvi Flensner
Elucidating patients´ experiences of living with chronic progressive hereditary ataxia and the symptomatic treatment with intrathecal baclofen (ITB) is the objective of the current study. A multicenter qualitative study with four patients included due to the rare combination of hereditary ataxia and ITB therapy was designed to elucidate participants’ experiences through semi-structured interviews. The transcribed text was analyzed according to content analysis guidelines. Overall we identified living in the present/ taking one day at a time as the main theme covering the following categories: 1) Uncertainty about the future as a consequence of living with a hereditary disease; The disease; 2) Impact on life as a whole, 3) Influence on personal life in terms of feeling forced to terminate employment, 4) Limiting daily activities, and 5) ITB therapy, advantages, and disadvantages. Uncertainty about the future was the category that affected participants’ personal life, employment, and daily activities. The participants’ experience of receiving ITB therapy was expressed in terms of improved quality of life due to better body position and movement as well as better sleep and pain relief.
Friedreich’s ataxia associated with marfanoid features & alopecia areata-rare disease manifestations or chance association?
Friedreich’s ataxia is the commonest cause of inherited ataxia and has an autosomal recessive mode of inheritance. The disease manifestations usually start appearing before the end of puberty and in most of the patients before 20 years of age. Classical disease presentation consists of slowly progressive sensory and cerebellar ataxia, absent deep tendon reflexes in lower limbs with subsequent development of dysarthria and other features. Apart from neurological features it has cardiac, skeletal and endocrine manifestations but its association with marfanoid features or alopecia areata has not been described in literature.
Muscle ultrasound comparison between patients with early and delayed onset Friedreich’s ataxia – Preliminary data
Lower medulla hypoplasia in Friedreich ataxia: MR Imaging confirmation 140 years later
- Andrea Bianchi
- Stefano Ciulli
- Andrea Ginestroni
- Marco Aiello
- Maria Teresa Dotti
- Fabrizio Salvi
- Emanuele Nicolai
- Andrea Soricelli
- Stefano Diciotti
Neurodegenerative disease mechanism and potential drug identified
Offers hope for patients with Friedreich’s Ataxia and related diseases
June 6, 2017
University of California – Davis
Two new studies of neurodegenerative diseases linked to mitochondrial defects offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases.
Two new studies of progressive, neurodegenerative diseases linked to defects in cells’ mitochondria offer hope for developing a new biomarker for research and diagnostics, and a drug for treating such diseases, report researchers at the University of California, Davis.
Both studies, co-authored by biochemist Gino Cortopassi in the UC Davis School of Veterinary Medicine, have implications for Friedreich’s ataxia, a rare, inherited disease that affects 6,000 people in the United States.
Friedreich’s is characterized by progressive neurodegeneration in the spine, as well as muscle weakness, heart disease and diabetes.
Findings from the two studies are being published this week in the journal Human Molecular Genetics
Tert-butylhydroquinone protects PC12 cells against ferrous sulfate-induced oxidative and inflammatory injury via the Nrf2/ARE pathway
tBHQ protected PC12 cells from ferrous sulfate-induced cell injury and apoptosis.
tBHQ alleviated ferrous sulfate-induced oxidative stress in PC12 cells.
tBHQ inhibited the inflammatory response caused by ferrous sulfate in PC12 cells.
Those neuroprotective effects of tBHQ were dependent on the Nrf2/ARE pathway.
Increasing evidence had proved the critical role of iron in the pathogenesis of numerous neurodegenerative diseases because of its capacity to promote the formation of reactive oxygen species (ROS). Tert-butylhydroquinone (tBHQ) was a metabolite of butylated hydroxyanisole, a widely used food antioxidant. This study was aimed to investigate the protective effects of tBHQ on a cellular model of neurodegenerative disease, which was established in PC12 cells by exposure to ferrous sulfate (FS), and elucidate the potential protective mechanisms. The results showed that FS exposure increased lactate dehydrogenase (LDH) release and cell apoptosis in PC12 cells, accompanied by significant increases in the bax/bcl-2 ratio, cytochrome c release, and caspase-3 cleavage. It also enhanced the ROS production, malondialdehyde (MDA) content (lipid peroxidation), γ-H2A.X formation (DNA damage), and promoted nuclear factor kappa B (NF-κB) activation and expressions of cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). tBHQ pretreatment alleviated FS-induced LDH release, cell apoptosis, oxidative stress and inflammatory response by promoting Nrf2 nuclear translocation and the protein levels of Nrf2 downstream target genes heme oxygenase-1 (Hmox-1), nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase-1 (Nqo1) and glutathione peroxidase-1 (Gpx1). tBHQ alleviated the FS-induced LDH release in control siRNA-treated PC12 cells, but failed to alleviate FS-induced LDH release in Nrf2 siRNA-treated cells. These findings suggested that pretreatment with tBHQ protected PC12 cells from FS-induced oxidative and inflammatory injury via the Nrf2/ARE pathway. tBHQ was promising as a potential therapeutic agent for neurodegenerative diseases induced by iron toxicity and should be encouraged for further research
Is Reata’s Friedreich’s Ataxia Study a Failure?
Data from a Phase 2 Friedreich’s ataxia (FA) study by Reata Pharmaceuticals is making its rounds on social media today. The data, according to Reata, is exceptional. However, according to many on Twitter, the trial is a failure.
Reata Pharmaceuticals, Inc. Announces Positive Data From Part One of Moxie Trial of Omaveloxolone for Friedreich’s Ataxia
Omaveloxolone Induced Nrf2 and Improved Mitochondrial and Neurological Function
Company Planning to Initiate Part 2 of Trial During the Second Half of 2017
Data Presentation and Conference Call Scheduled for June 2nd
IRVING, Texas, June 01, 2017 (GLOBE NEWSWIRE) — Reata Pharmaceuticals, Inc. (Nasdaq:RETA) (“Reata” or “the Company”), a clinical-stage biopharmaceutical company, today announced positive data from Part 1 of the Company’s Phase 2 trial (MOXIe) of omaveloxolone for the treatment of Friedreich’s ataxia (FA). The trial demonstrated that in FA patients, omaveloxolone induced Nrf2, which is suppressed in FA patients, and this was associated with improvements in mitochondrial and neurological function. Dose-dependent and time-dependent effects on the modified Friedreich’s Ataxia Rating Scale (mFARS) were observed at the pharmacodynamically active doses, and the maximum effect on mFARS was observed at the 160 mg dose level. The Company is planning to initiate Part 2 of MOXIe during the second half of 2017.
“We are greatly appreciative of Reata, the clinical investigators, and the study volunteers for conducting and participating in a well-designed and robust dose-escalation study. We find these results to be very exciting, and they are the ideal outcome for an early Phase 2 study. They exceed expectations in terms of safety and by demonstrating dose-dependent and clinically meaningful activity that correlated with biological activity,” said Jennifer Farmer, the Executive Director of the Friedreich’s Ataxia Research Alliance (FARA). “FARA and the FA community encourage urgency in advancing this program to Part 2 of the study to allow for further evaluation of efficacy and safety, as there are no approved therapies to slow progression or improve symptoms for individuals living with FA. Every day counts for our patient families.”
The complete data will be presented by Dr. David Lynch, Director of the Friedreich’s Ataxia Program at Children’s Hospital of Philadelphia, during the afternoon of June 2, 2017 at 3:00pm EDT, after completion of the Patient-Focused Drug Development meeting hosted by FARA.
Friedreich’s ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency
Duncan E. Crombie 1, 2 , Claire L. Curl 3 , Antonia JA Raaijmakers 3 ,Priyadharshini Sivakumaran 4 , Tejal Kulkarni 1, 2, 5 ,Raymond CB Wong 1, 2 , Itsunari Minami 6 , Marguerite V. Evans-Galea 7 ,Shiang Y. Lim 2, 4 , Lea Delbridge 4 , Louise A. Corben 7, 8 , Mirella Dottori 5 ,Norio Nakatsuji 6 , Ian A. Trounce 1, 2 , Alex W. Hewitt 1, 2, 9 ,Martin B. Delatycki 7, 8, 10 , Martin F. Pera 11 , Alice Pébay 1, 2
- 1 Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia
- 2 Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
- 3 Department of Physiology, the University of Melbourne, Melbourne, Australia
- 4 O’Brien Institute Department, St Vincent Institute of Medical Research, Fitzroy, Australia
- 5 Centre for Neural Engineering & Department of Electrical and Electronic Engineering, The University of Melbourne, Melbourne, Australia
- 6 Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan
- 7 Bruce Lefroy Centre for Genetic Health Research, Murdoch Children’s Research Institute, & Department of Paediatrics, The University of Melbourne, Melbourne, Australia
- 8 School of Psychological Sciences, Monash University, Frankston, Australia
- 9 Menzies Institute for Medical Research, School of Medicine, University of Tasmania, Hobart, Australia
- 10 Victorian Clinical Genetics Services, Parkville, Australia
- 11 Department of Anatomy and Neurosciences, the University of Melbourne, Florey Neuroscience & Mental Health Institute, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
We sought to identify the impacts of Friedreich’s ataxia (FRDA) on cardiomyocytes. FRDA is an autosomal recessive degenerative condition with neuronal and non-neuronal manifestations, the latter including progressive cardiomyopathy of the left ventricle, the leading cause of death in FRDA. Little is known about the cellular pathogenesis of FRDA in cardiomyocytes. Induced pluripotent stem cells (iPSCs) were derived from three FRDA individuals with characterized GAA repeats. The cells were differentiated into cardiomyocytes to assess phenotypes. FRDA iPSC- cardiomyocytes retained low levels of FRATAXIN (FXN) mRNA and protein. Electrophysiology revealed an increased variation of FRDA- cardiomyocyte beating rates which was prevented by addition of nifedipine, suggestive of a calcium handling deficiency. Finally, calcium imaging was performed and we identified small amplitude, diastolic and systolic calcium transients confirming a deficiency in calcium handling. We defined a robust FRDA cardiac-specific electrophysiological profile in patient-derived iPSCs which could be used for high throughput compound screening. This cell-specific signature will contribute to the identification and screening of novel treatments for this life-threatening disease.
Single-step blood direct PCR: A robust and rapid method to diagnose triplet repeat disorders
- Inder Singha, 1,
- Vishnu Swarupa, 1,
- Sunil Shakyaa,
- Vinay Goyala,
- Mohammed Faruqb,
- Achal Kumar Srivastavaa, ,
BD-PCR is a single step procedure for molecular diagnoses of triplet repeat disorder.
No DNA extraction or pretreatment of blood sample is required.
The performance of the BD-PCR is rapid and more reliable than the conventional method.
BD-PCR overcomes limitations of DNA as genetic diagnosis source in genetic disorders.
DNA extraction prior to polymerase chain reaction (PCR) amplification in genetic diagnoses of triplet repeat disorders (TRDs) is tedious and labour-intensive and has the limitations of sample contamination with foreign DNA, including that from preceding samples. Therefore, we aimed to develop a rapid, robust, and cost-effective method for expeditious genetic investigation of TRDs from whole blood as a DNA template.
Peripheral blood samples were collected from 70 clinically suspected patients of progressive ataxia. The conventional method using genomic DNA and single-step Blood-Direct PCR (BD-PCR) method with just 2 μl of whole blood sample were tested to amplify triplet repeat expansion in genes related to spinocerebellar ataxia (SCA) types 1, 2, 3, 12 and Friedreich’s ataxia (FRDA). Post-PCR, the allele sizes were mapped and repeat numbers were calculated using GeneMapper and macros run in Microsoft Excel programmes.
Successful amplification of target regions was achieved in all samples by both methods. The frequency of the normal and mutated allele was concordant between both methods, diagnosing 37% positive for a mutation in either of the candidate genes. The BD-PCR resulted in higher intensities of product peaks of normal and pathogenic alleles.
The nearly-accurate sizing of the normal and expanded allele was achieved in a shorter time (4–5 h), without DNA extraction and any risk of cross contamination, which suggests the BD-PCR to be a reliable, inexpensive, and rapid method to confirm TRDs. This technique can be introduced in routine diagnostic procedures of other tandem repeat disorders.