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.