Exploring the Potential of Small Molecule-Based Therapeutic Approaches for Targeting Trinucleotide Repeat Disorders

Arun Kumar Verma & Eshan Khan & Sonali R. Bhagwat & Amit Kumar; Mol Neurobiol (2019). doi:10.1007/s12035-019-01724-4

In recent years, neurological disorders have globally become a leading cause of disability and death. Neurological disorders are very common in both high- and low-income countries, and the number of patients is predicted to increase in the coming decades. Disorders caused by the expanded trinucleotide repeats (CAG, CGG, CCG, CTG, CUG, GAA, and GCN) in the genome, also described as trinucleotide repeat expansion disorders (TREDs), comprise of the major class of neurological diseases. Various TREDs have different modes of pathogenesis, but the severity and time of onset of disease depends on the trinucleotide repeat numbers. Numerous therapeutic strategies, including symptomatic treatment, blockage of mutant protein synthesis, targeting the toxic protein aggregates and degradation of RNA transcripts have been developed for the treatment of these diseases. However, various limitations to these therapeutic strategies have been reported, and therefore, researchers are exploring different avenues of therapeutics development. One of the recent developments include targeting the expanded repeats with small molecules. Small molecule binds with the secondary/tertiary structure of RNA (like bulges, loops, and hairpins) irrespective of its sequences. Altogether, small molecule-based therapeutics may have the advantage over others to be able to overcome the hurdles of the blood–brain barrier, poor absorption, and allergic reactions. In this review, we have summarized various TREDs and envisage the potential of small molecule-based therapeutics for targeting these hitherto incurable neurological disorders.

Excision of the expanded GAA repeats corrects cardiomyopathy phenotypes of iPSC-derived Friedreich's ataxia cardiomyocytes

Jixue Li, Natalia Rozwadowska, Amanda Clark, Daniel Fil, Jill S. Napierala, Marek Napierala; Stem Cell Research, 2019, 101529, doi:10.1016/j.scr.2019.101529.

Our studies were conducted using cardiomyocytes differentiated from induced pluripotent stem cells derived from control individuals, FRDA patients, and isogenic cells corrected by zinc finger nucleases-mediated excision of pathogenic expanded GAA repeats. This correction of the FXN gene removed the primary trigger of the transcription defect, upregulated frataxin expression, reduced pathological lipid accumulation observed in patient cardiomyocytes, and reversed gene expression signatures of FRDA cardiomyocytes. Transcriptome analyses revealed hypertrophy-specific expression signatures unique to FRDA cardiomyocytes, and emphasized similarities between unaffected and ZFN-corrected FRDA cardiomyocytes. Thus, the iPSC-derived FRDA cardiomyocytes exhibit various molecular defects characteristic for cellular models of cardiomyopathy that can be corrected by genome editing of the expanded GAA repeats. These results underscore the utility of genome editing in generating isogenic cellular models of FRDA and the potential of this approach as a future therapy for this disease.

Physiologically relevant reconstitution of iron-sulfur cluster biosynthesis uncovers persulfide-processing functions of ferredoxin-2 and frataxin

Sylvain Gervason, Djabir Larkem, Amir Ben Mansour, Thomas Botzanowski, Christina S. Müller, Ludovic Pecqueur, Gwenaelle Le Pavec, Agnès Delaunay-Moisan, Omar Brun, Jordi Agramunt, Anna Grandas, Marc Fontecave, Volker Schünemann, Sarah Cianférani, Christina Sizun, Michel B. Tolédano & Benoit D’Autréaux;Nature Communicationsvolume 10, Article number: 3566 (2019), doi:10.1038/s41467-019-11470-9

Here, we report the breakdown of this process, made possible by removing a zinc ion in ISCU that hinders iron insertion and promotes non-physiological Fe-S cluster synthesis from free sulfide in vitro. By binding zinc-free ISCU, iron drives persulfide uptake from NFS1 and allows persulfide reduction into sulfide by FDX2, thereby coordinating sulfide production with its availability to generate Fe-S clusters. FXN stimulates the whole process by accelerating persulfide transfer. We propose that this reconstitution recapitulates physiological conditions which provides a model for Fe-S cluster biosynthesis, clarifies the roles of FDX2 and FXN and may help develop Friedreich’s ataxia therapies.

A Collaborative-Filtering-Based Data Collection Strategy for Friedreich’s Ataxia

Wenbin Yue, Zidong Wang, Bo Tian, Annette Payne, Xiaohui Liu. Cogn Comput (2019). doi:10.1007/s12559-019-09674-8

We propose a novel data collection strategy for the FRDA baseline data by using the collaborative filtering (CF) approaches. This strategy is motivated by the popularity of the nowadays “Recommendation System” whose central idea is based on the fact that similar patients have similar symptoms on each test item. By doing so, instead of having no data at all, the FRDA researchers would be provided with certain predicted baseline data on patients who cannot attend the assessments for physical/psychological reasons, thereby helping with the data analysis from the researchers’ perspective. It is shown that the CF approaches are capable of predicting baseline data based on the similarity in test items of the patients, where the prediction accuracy is evaluated based on three rating scales selected from the EFACTS database. Experimental results demonstrate the validity and efficiency of the proposed strategy.

Reata gets another shot in Friedreich’s ataxia

EvaluatePharma. August 06, 2019.

Pharmaceuticals will soon find out if its decision to persevere with omaveloxolone despite an earlier failure has paid off.

The signs are not auspicious: the first part of the same study did not show a benefit with omaveloxolone on the primary endpoint, peak work during maximal exercise testing, or its secondary endpoint, change versus placebo on the modified Friedreich’s ataxia rating scale (mFARS), when it reported two years ago (Friedreich's failure highlights thinning pipeline, 2 June 2017).

Despite this, Reata claimed that the data were positive, and Vinny Jindal, the group’s vice-president of strategy, told Vantage: “I wouldn’t classify part one of Moxie as a failure.” He added that the study had found a “meaningful” effect on patients, as measured by mFARS, a 100-point scale on which a higher score represents more severe disease.

Mr Jindal pointed to a 2.3-point placebo-corrected reduction on mFARS after 12 weeks' treatment with omaveloxolone 160mg, the best-performing dose in part one. This missed statistical significance with a p value of 0.06.

Nevertheless, Mr Jindal maintained: “Patients typically progress 1-2 points per year, so that improvement [could save patients] more than a year of progression.”

Pharmaceutical compounding of orphan active ingredients in Belgium: how community and hospital pharmacists can address the needs of patients with rare diseases

V. Vanhoorne, E. Peeters, I. Van Tongelen, K. Boussery, E. Wynendaele, B. De Spiegeleer, J. P. Remon & C. Vervaet ; Orphanet Journal of Rare Diseasesvolume 14, Article number: 186 (2019) DOI 10.1186/s13023-019-1154-x

Pharmaceutical compounding of orphan active ingredients can offer cost-effective treatment to patients when no other drug product is available for a rare disease or during periods of drug product shortages. Additionally, it allows customized therapy for patients with rare diseases. However, standardized compounding formulas and procedures, and monographs are required to ensure the patients’ safety.
Compounded preparations of OAIs can improve patients’ access to treatment for rare diseases. However, they should be prepared in accordance to standardized formulas and compounding procedures and the quality of the OAI should be demonstrated by a certificate of analysis according to a specific monograph. In current study, such standardized formulas and compounding procedures were developed for seven OAIs to treat patients with rare diseases when no other treatment is available. More efforts are needed to develop standardized formulas and compounding procedures for additional OAIs whose clinical efficacy is well-known but are not available yet to patients due to lack of interest from the pharmaceutical industry to apply for market authorization as OMP. Additionally, a legal framework at EU level is required to enable the potential of pharmaceutical compounding for OAIs.

Exploring iron-binding to human frataxin and to selected Friedreich ataxia mutants by means of NMR and EPR spectroscopies

Massimo Bellanda, Lorenzo Maso, Davide Doni, Marco Bortolus, Edith De Rosa, Federica Lunardi, Arianna Alfonsi, Martín Ezequiel Noguera, Maria Georgina Herrera, Javier Santos, Donatella Carbonera, Paola Costantini; Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 2019, doi:10.1016/j.bbapap.2019.07.007.

n this work we combined different advanced spectroscopic analyses to explore the iron-binding properties of human frataxin, as isolated and at the FeS clusters assembly machinery. For the first time we used EPR spectroscopy to address this key issue providing clear evidence of the formation of a complex with a low symmetry coordination of the metal ion. By 2D NMR, we confirmed that iron can be bound in both oxidation states, a controversial issue, and, in addition, we were able to point out a transient interaction of frataxin with a N-terminal 6his-tagged variant of ISCU, the scaffold protein of the FeS clusters assembly machinery. To obtain insights on structure/function relationships relevant to understand the disease molecular mechanism(s), we extended our studies to four clinical frataxin mutants. All variants showed a moderate to strong impairment in their ability to activate the FeS cluster assembly machinery in vitro, while keeping the same iron-binding features of the wild type protein. This supports the multifunctional nature of frataxin and the complex biochemical consequences of its mutations.

Exploring iron-binding to human frataxin and to selected Friedreich ataxia mutants by means of NMR and EPR spectroscopies

BioMarin announced plans to discontinue preclinical studies in the BMN290 programme for Friedreich’s Ataxia

August 2019. BioMarin’s BMN 290 Programme: An Update for the Friedreich’s Ataxia Community On August 1, 2019 BioMarin announced plans to discontinue preclinical studies in the BMN290 programme for Friedreich’s Ataxia. BMN 290 is a selective chromatin modulationtherapy that has been under investigation as an active preclinical programme since 2017.All drug development companies actively manage their portfolios to ensure resources are directed as efficiently as possible. Despite a significant clinical research effort in Friedreich’s Ataxia, other research programmes within BioMarin continue to demonstrate a clearer path forward. It is with great regret that we are unable to pursue this programme further.

Henry Fuchs -- Executive Vice President and Chief Medical Officer: After my preclinical research and testing, we have determined this in the best interest of our R&D organization to put our resources toward products that have demonstrated a clear path forward. To take decisions very seriously, we will continue to take a disciplined approach when determining which portfolio assets align with our stage of growth and in the best interest of our shareholders and patients.

Low frataxin mRNA expression is associated with inflammation and oxidative stress in patients with type 2 diabetes

Etiane Tatsch José A.M. De Carvalho Yãnaí S. Bollick Thiago Duarte Marta M.M.F. Duarte Rodrigo A. Vaucher Melissa O. Premaor Fabio V. Comim Rafael N. Moresco; Diabetes Metab Res Rev. 2019;e3208. doi:10.1002/dmrr.3208.

Type 2 diabetes patients with low frataxin mRNA levels showed a high degree of inflammation and oxidative stress. It is speculated that frataxin deficiency in T2D patients can contribute to the imbalance in mitochondrial iron homeostasis leading to the acceleration of oxidative stress and inflammation.

REGENXBIO Announces New License Agreement with Pfizer for the Treatment of Friedreich's Ataxia Using NAV® AAV9 Vector

ROCKVILLE, Md., July 31, 2019 /PRNewswire/ -- REGENXBIO Inc. (Nasdaq: RGNX), a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy based on its proprietary NAV Technology Platform, today announced it entered into a license agreement with Pfizer Inc.
"This license agreement further validates the strength of our intellectual property portfolio and the potential of NAV AAV9 for the treatment of systemic and CNS manifestations of movement disorders," said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. "We are pleased to establish our relationship with Pfizer as they advance this program to develop a potential gene therapy treatment for Friedreich's ataxia."