StrideBio and Takeda Enter Collaboration and License Agreement to Advance Novel Gene Therapies for Neurological Diseases

DURHAM, N.C., March 28, 2019 /PRNewswire/ — StrideBio, Inc, a leading developer of novel adeno-associated viral (AAV) based gene therapies, today announced the signing of a collaboration and license agreement with Takeda Pharmaceutical Company Limited (Takeda) to develop in vivo AAV based therapies for Friedreich’s Ataxia (FA) and two additional undisclosed targets. These programs aim to utilize novel AAV capsids developed by StrideBio to improve potency, evade neutralizing antibodies and enhance specific tropism to tissues including the central nervous system.

New Insights into the Hepcidin-Ferroportin Axis and Iron Homeostasis in iPSC-Derived Cardiomyocytes from Friedreich’s Ataxia Patient

Alessandra Bolotta, Provvidenza Maria Abruzzo, Vito Antonio Baldassarro, Alessandro Ghezzo, Katia Scotlandi, Marina Marini and Cinzia Zucchini, Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 7623023, 11 pages, 2019. doi:10.1155/2019/7623023.

Iron homeostasis in the cardiac tissue as well as the involvement of the hepcidin-ferroportin (HAMP-FPN) axis in this process and in cardiac functionality are not fully understood. Imbalance of iron homeostasis occurs in several cardiac diseases, including iron-overload cardiomyopathies such as Friedreich’s ataxia (FRDA, OMIM no. 229300), a hereditary neurodegenerative disorder. Exploiting the induced pluripotent stem cells (iPSCs) technology and the iPSC capacity to differentiate into specific cell types, we derived cardiomyocytes of a FRDA patient and of a healthy control subject in order to study the cardiac iron homeostasis and the HAMP-FPN axis. Both CTR and FRDA iPSCs-derived cardiomyocytes express cardiac differentiation markers; in addition, FRDA cardiomyocytes maintain the FRDA-like phenotype. We found that FRDA cardiomyocytes show an increase in the protein expression of HAMP and FPN. Moreover, immunofluorescence analysis revealed for the first time an unexpected nuclear localization of FPN in both CTR and FRDA cardiomyocytes. However, the amount of the nuclear FPN was less in FRDA cardiomyocytes than in controls. These and other data suggest that iron handling and the HAMP-FPN axis regulation in FRDA cardiac cells are hampered and that FPN may have new, still not fully understood, functions. These findings underline the complexity of the cardiac iron homeostasis.

Open Trail of γIFN for Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT03888664. IRCCS Eugenio Medea

The investigator proposes an open label pilot study to investigate the safety and efficacy of gamma interferon (γIFN) in patients with Friedreich's Ataxia (FRDA). yIFN, an approved drug for treatment of granulomatous disease, has been shown to promote Frataxin expression in FRDA models in vitro and in vivo as well as in pilot human studies.
Safety will monitored by clinical surveillance and biohumoral periodic assessment. Efficacy will be assessed by a combination of advanced neuroimaging techniques and established clinical indicators. The investigators intend to recruit over a 6 months period 12 subject with molecularly established FRDA. The protocol builds on a recently concluded observational study which established the pattern of clinical and neuroimaging abnormalities characterizing a cohort of patients with FA. The data already acquired through such study will constitute the T -12 point, and together with T0 assessment, carried out at study entrance, will provide for each patient the exact appreciation of disease actual progression over a year time. Recruited patients will receive for 6 months yIFN at a final dose of 200 ug/three times a week. Patients will be evaluated clinically after 3 and 6 months (t3 and T6) of treatment and 6 months after treatment end (T+6) and by neuroimaging at T6 and T+6. The neuroimaging protocol, based on 3 Tesla scanner, consists in functional MRI, tractography and brain iron content measurement. The clinical protocol consists on specific ataxia scales administration. Regular monitoring with for eventual adverse events will be provided. Frataxin levels in the peripheral blood mononuclear cells will also be evaluated at T0, T3, T6, T+6. In addition cardiac ventricular thickness and contrast vision will be followed at T0, T6, T+6.

Therapeutic Prospects for Friedreich’s Ataxia

Siyuan Zhang, Marek Napierala, Jill S. Napierala; Trends in Pharmacological Sciences, Volume 40, Issue 4, 2019, Pages 229-233, doi:10.1016/j.tips.2019.02.001.

Friedreich’s ataxia (FRDA) is a progressive disease affecting multiple organs that is caused by systemic insufficiency of the mitochondrial protein frataxin. Current therapeutic strategies aim to elevate frataxin levels and/or alleviate the consequences of frataxin deficiency. Recent significant advances in the FRDA therapeutic pipeline are bringing patients closer to a cure.

Ion Mobility-Mass Spectrometry Reveals Details of Formation and Structure for GAA·TCC DNA and RNA Triplexes

Jiawei Li, Alexander Begbie, Belinda J. Boehm, Alexander Button, Charles Whidborne, Yannii Pouferis, David M. Huang, Tara L. Pukala; J. Am. Soc. Mass Spectrom. (2019) 30: 103. doi:10.1007/s13361-018-2077-9

DNA and RNA triplexes are thought to play key roles in a range of cellular processes such as gene regulation and epigenetic remodeling and have been implicated in human disease such as Friedreich’s ataxia. In this work, ion mobility-mass spectrometry (IM-MS) is used with supporting UV-visible spectroscopy to investigate DNA triplex assembly, considering stability and specificity, for GAA·TTC oligonucleotide sequences of relevance to Friedreich’s ataxia.

Patient reported outcomes in Friedreich's Ataxia after withdrawal from Idebenone

Cook, A. , Boesch, S. , Heck, S. , Brunt, E. , Klockgether, T. , Schöls, L. , Schulz, A. and Giunti, P. (2019). Acta Neurol Scand. Accepted Author Manuscript. doi:10.1111/ane.13088

This study provides no data to suggest that FRDA patients could correctly determine their treatment assignment over a 2‐month period. We hope that this study design will help inform future trials so that patients’ experiences of symptoms are more reliably measured.

CRISPR-cas gene-editing as plausible treatment of neuromuscular and nucleotide-repeat-expansion diseases: A systematic review.

Babačić H, Mehta A, Merkel O, Schoser B (2019); PLOS ONE 14(2): e0212198. doi:10.1371/journal.pone.0212198

Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne’s muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington’s disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies.

Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.

Inherited Ataxia and Intrathecal Baclofen for the Treatment of Spasticity and Painful Spasms

Berntsson S, G, Gauffin H, Melberg A, Holtz A, Landtblom A, M; Stereotact Funct Neurosurg 2019. doi: 10.1159/000497165

Intrathecal baclofen (ITB) treatment is considered a powerful tool in the management of severe spasticity in neurological conditions such as multiple sclerosis, cerebral palsy, and traumatic spinal cord and brain injury. The objective of this study was to assess the effectiveness of the ITB in patients with inherited ataxia suffering from severe painful spasms and/or spasticity. A total of 5 patients with spinocerebellar ataxia 3 or 7 or Friedreich’s ataxia were included in this observational multicenter study We report the potential beneficial effects of ITB treatment in patients with inherited ataxia who also suffer from spasticity/spasms. ITB treatment indication in neurological disorders allows for extension to the treatment of spasticity/ spasms in patients with hereditary ataxia.

Assessment of cell-free levels of iron and copper in patients with Friedreich’s ataxia

Deepti PathakAchal Kumar SrivastavaSheffali GulatiMoganty R. Rajeswari; Biometals (2019). https://doi.org/10.1007/s10534-019-00186-4

The iron levels mean ± SD (6.2 ± 3.8) in plasma of FRDA patients were found to be significantly decreased as compared to healthy controls mean ± SD (15.2 ± 4.2). A similar trend was observed in case of plasma copper levels in FRDA patient (8.15 ± 4.6) as compared to controls (17.5 ± 3.40). Present results clearly prove abnormal distribution of extra-cellular iron in FRDA patients, which is in accordance with the well established fact of intracellular iron overload, which is the key feature of the pathogenesis of this disease. This can be of importance in understanding the pathophysiology of the disease in association with frataxin/iron. It appears that intracellular sequestration of trace metals in FRDA patients (due to low frataxin) results in their sub-optimal levels in blood plasma (extra-cellular) an observation that can find prognostic application in clinical trials.

The role of robotic gait training and tDCS in Friedrich ataxia rehabilitation: A case report

Simona Portaro;Margherita Russo;Alessia Bramanti;Antonio Leo;Luana Billeri;Alfredo Manuli;Gianluca La Rosa;Antonino Naro;Rocco Calabrò; Medicine. 98(8):e14447, FEB 2019 DOI: 10.1097/MD.0000000000014447, Publication Date: 2019/02/01

Friedrich ataxia (FA) is the most common inherited neurodegenerative cerebellar ataxic syndrome. In patients with FA, physiotherapy is highly recommended to improve motor function outcome. Cerebellar transcranial direct current stimulation (tDCS) has been demonstrated to be effective in improving symptoms by modulating cerebellar excitability. Recently, robotic rehabilitation with Lokomat-Pro has been used to treat motor impairment in ataxic syndromes by “modulating” cortical plasticity and cerebello-motor connectivity.
Only a single case is described, we found that the combined neuromodulation-neurorobotic approach could become a promising tool in the rehabilitation of cerebellar ataxias, possibly by shaping cerebello-cerebral plasticity and connectivity.

Combining nanoparticle and stem cell technologies to develop therapies for Friedreich’s ataxia

IHMRI - Illawarra Health and Medical Research Institute.08/03/2019. Professor Mirella Dottori has been awarded a USA National Ataxia Foundation Grant to continue her research into the neurodegenerative disease, Friedreich’s ataxia (FRDA).
In collaboration with Dr Christina Cortez-Jugo, University of Melbourne, they are using nanoparticles as a vechicle to deliver Frataxin to the diseased cells to see if they can reverse symptoms caused by the faulty gene and could potentially lead to a cure or treatment.

Abnormal Eye Movements in Parkinsonism and Movement Disorders

Ileok Jung, Ji-Soo Kim; J Mov Disord. 2019;12(1):1-13. Published online January 30, 2019 DOI: 10.14802/jmd.18034

Friedreich ataxia (FA) is the most common cause of autosomal recessive ataxias with an onset usually before age 20 years. FA is characterized by ataxia, hyporeflexia, extensor plantar reflexes, neuropathy, cardiomyopathy, and diabetes. FA is mostly due to an unstable GAA repeat expansion within intron 1 of frataxin. Abnormal ocular motor findings of FA include fixation instability manifesting as SWJs and ocular flutter . While saccadic velocity is essentially normal, saccadic latency is prolonged. The latency correlates with clinical measures of disease severity. Saccades may be both hypo- and hypermetric. SP and the VOR may be impaired Caloric tests are abnormal in the majority of FA patients. Thus, severe vestibulopathy with essentially normal saccadic velocity are hallmarks of FA and differentiate it from a number of dominant SCA.

Progress in understanding Friedreich’s ataxia using human induced pluripotent stem cells

Anna M. Schreiber, Julia O. Misiorek, Jill S. Napierala & Marek Napierala (2019), Expert Opinion on Orphan Drugs, 7:2, 81-90, DOI: 10.1080/21678707.2019.1562334

The versatility of iPSC-derived cellular models of FRDA is advantageous for developing new therapeutic strategies, and rigorous testing in such models will be critical for approval of the first treatment for FRDA. Creating a well-characterized and diverse set of iPSC lines, including appropriate isogenic controls, will facilitate achieving this goal. Also, improvement of differentiation protocols, especially towards proprioceptive sensory neurons and organoid generation, is necessary to utilize the full potential of iPSC technology in the drug discovery process.

Quantitative assessment of cerebellar ataxia, through automated limb functional tests

Ragil Krishna, Pubudu N. Pathirana, Malcolm Horne, Laura Power and David J. Szmulewicz; Journal of NeuroEngineering and Rehabilitation 2019 16:31 doi:10.1186/s12984-019-0490-3

This paper investigates automated versions of three commonly used tests: Finger to Nose test (FNT), test for upper limb Dysdiadochokinesia Test (DDK) and Heel to Shin Test (HST), in evaluating disability due to CA.

Conclusion: For the predominantly translational movement in the upper limb FNT, the rotation captures disability and for the DDK test with predominantly rotational movements, the linear acceleration captures the disability but cannot be extended to the lower limb HST. The orthogonal direction manifestation of ataxia attributed to sensory measurements was determined for each test.

Identification of a novel missense mutation in Friedreich's ataxia –FXNW168R

Clark, E. , Strawser, C. , Schadt, K. and Lynch, D. R. (2019), Ann Clin Transl Neurol. doi:10.1002/acn3.728

Friedreich's ataxia, characterized by decreased expression of frataxin protein, is caused by GAA trinucleotide repeats within intron 1 in 98% of patients. Two percent of patients carry GAA repeats in conjunction with a point mutation. In this work, we find that frataxinW168R, a novel disease‐causing missense mutation, is expressed predominantly as the intermediate frataxin42‐210 form, with very little expression of mature frataxin81‐210 form. Its localization to mitochondria is not impaired. Additionally, increasing frataxinW168R precursor levels do not lead to an increase in mature frataxin levels, suggesting these patients will require alternative approaches to repair frataxin processing in order to treat the disorder in a disease‐modifying manner.

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Nicholas G Fox, Xiaodi Yu, Xidong Feng, Henry J Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue, Seungil Han; bioRxiv 561795; doi: 10.1101/561795

Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.

Case 3: Gait Instability and Elevated Troponin Level in a 16-year-old Boy

Carrie Johnson, Shaun Mohan; Pediatrics in Review Feb 2019, 40 (2) 85-87; DOI: 10.1542/pir.2017-0095

Given the findings of hypertrophic cardiomyopathy, ataxia, and abnormal neurologic examination findings, there was suspicion for Friedreich ataxia (FRDA). Genetics was consulted, who agreed, and recommended repeated expansion analysis. During follow-up his genetic testing results were positive for 2 alleles with GAA trinucleotide repeat expansion: allele 1 with 1070 GAA repeats and allele 2 with 830 GAA repeats, consistent with diagnosis of FRDA.

In Vitro interaction between yeast frataxin and superoxide dismutases: Influence of mitochondrial metals

Thi Hong Lien Han, Jean-Michel Camadro, Florent Barbault, Renata Santos, Jean-Michel El Hage Chahine, Nguyet-Thanh Ha-Duong; Biochimica et Biophysica Acta (BBA) - General Subjects, Volume 1863, Issue 5, 2019, Pages 883-892, ISSN 0304-4165, doi:10.1016/j.bbagen.2019.02.011.

Friedreich's ataxia results from a decreased expression of the nuclear gene encoding the mitochondrial protein, frataxin. Frataxin participates in the biosynthesis of iron-sulfur clusters and heme cofactors, as well as in iron storage and protection against oxidative stress. How frataxin interacts with the antioxidant defence components is poorly understood.

Randomized, double‐blind, placebo‐controlled study of interferon‐γ 1b in Friedreich Ataxia

Lynch, D. R., Hauser, L. , McCormick, A. , Wells, M. , Dong, Y. N., McCormack, S. , Schadt, K. , Perlman, S. , Subramony, S. H., Mathews, K. D., Brocht, A. , Ball, J. , Perdok, R. , Grahn, A. , Vescio, T. , Sherman, J. W. and Farmer, J. M. (2019); Ann Clin Transl Neurol. doi:10.1002/acn3.731

Results
No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open‐label extension period, subjects had a more stable course than expected based on natural history data.

Conclusions
This study provides no direct evidence for a beneficial effect of IFN‐γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

Structure of the human frataxin-bound iron-sulfur cluster assembly complex provides insight into its activation mechanism

Nicholas G Fox, Xiaodi Yu, Xidong Feng, Henry J Bailey, Alain Martelli, Joseph F. Nabhan, Claire Strain-Damerell, Christine Bulawa, Wyatt W. Yue, Seungil Han; bioRxiv 561795; doi:10.1101/561795

Our structure sheds light on how FXN facilitates ISC production through unlocking the zinc inhibition and stabilizing key loop conformations of NFS1 and ISCU at the protein-protein interfaces, and offers an explanation of how FRDA clinical mutations affect complex formation and FXN activation.

Researchers from Lleida make advances to propose new therapies in the treatment of Friedreich's ataxia

Communication and Press IRBLleida, February 28, the World Day of Minority Diseases.

The Oxidative Stress Biochemical Research Group, of the University of Lleida (UdL) and the Biomedical Research Institute of Lleida (IRBLleida), is carrying out two projects to better understand Friedreich's ataxia - which is caused by the deficiency of Frataxin, a mitochondrial protein.
The Oxidative Stress Biochemical Research Group investigates this minority disease since 2005. In 2011, it obtained a research project from the La Marató Foundation of TV3 (led by Jordi Tamarit); In addition to the projects named above, it also has support from Ataxia UK, the United Kingdom, co-funded by the Association of Catalan Ataxias (ACAH) and a project of the Ministry -Retos- called "Targeting mitochondria in Friedreich ataxia: molecular mechanisms and therapeutic approaches ". The results of the previous projects have provided new data on the mitochondrial alterations that occur due to frataxin deficit. Therefore, in these projects, the proposed objectives seek to find answers to know which are the mechanisms that explain the neurocardiodegenerative effects of frataxin deficiency and what is the capacity of some compounds to reverse these alterations and that can be proposed as treatments of the Friedreich ataxia.

C-Path, FARA launch Friedreich's Ataxia Clinical Database for Development of Treatments

EurekAlert, PUBLIC RELEASE: 27-FEB-2019, Ariz. and DOWNINGTOWN, Penn., February 27, 2019 -- Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) today announced the launch of the Friedreich's Ataxia Integrated Clinical Database (FAICD). The new platform will enable collaborative research and data sharing to support the understanding of natural history, potential biomarkers and clinical endpoints, and promote research into novel clinical trial design in Friedreich's ataxia (FA). By making this data available to researchers, the organizations hope to enable the development of tools that will help design and interpret efficient clinical trials -- leading to effective treatments for FA as soon as possible.