Chondrial Therapeutics Secures Up to $22.6 Million in Series A Financing and Licenses Novel Technology for the Treatment of Friedreich's Ataxia

PR Newswire, News provided by Chondrial Therapeutics, Inc. Feb 06, 2017, Company Plans to Advance Pipeline of Product Candidates Focused on the Treatment of Rare Mitochondrial Diseases, Carole Ben-Maimon, MD, Named President & CEO

Discovered by Dr. Payne while at Wake Forest Baptist Medical Center, CTI-1601 utilizes a carrier protein to deliver frataxin, the deficient protein in Friedreich's Ataxia, to the mitochondria where researchers believe it is processed to mature frataxin and becomes active in mitochondrial metabolism. People with Friedreich's Ataxia have very low levels of frataxin, which is active in the mitochondria and assists in energy production. Chondrial's premise in the research program is that by replacing the deficient protein the mitochondria will resume normal function, patients' symptoms may be minimized, and disease progression may be curtailed.

This comes a few months after Horizon Pharma’s Actimmune missed the primary endpoint in a phase 3 trial in the rare neurodegenerative movement disorder, sparking a 20% drop in its stock price.

MiRNA-145 Regulates the Development of Congenital Heart Disease Through Targeting FXN

Lei Wang, Danqiu Tian, Jihua Hu, Haijian Xing, Min Sun, Juanli Wang, Qiang Jian, Hua Yang. Pediatr Cardiol (2016) 37: 629. doi:10.1007/s00246-015-1325-z

we examined the effect of miRNA-145 and miRNA-182 on cell apoptosis, aconitase activity and ROS, and the results showed that transfection of miRNA-145 significantly activated caspase-3, which promotes apoptosis, and meanwhile suppressed aconitase activity and ROS formation, while miRNA-182 showed no such differences. These results indicate that the regulation of miRNA-145 on FXN influences the multiple aspects of cellular physiology.

Estudio piloto sobre los valores acústicos de las vocales en español como indicadores de la gravedad de la disartria

Pilot study of the acoustic values of the vowels in Spanish as indicators of the severity of dysarthria. (Article in Spanish; Abstract available in Spanish from the publisher.)

Delgado-Hernandez J.; Rev Neurol. 2017 Feb 1;64(3):105-111. PMID: 28128427

El análisis acústico es una herramienta que proporciona datos objetivos sobre las alteraciones del habla en la disartria. Los sujetos con disartria atáxica presentan un menor contraste vocálico y una centralización en la realización de las vocales. Las medidas acústicas estudiadas en este trabajo preliminar tienen una alta sensibilidad en la detección de la disartria, pero sólo el VSA y la media de las distancias primarias informan sobre la gravedad de este tipo de alteración del habla.

The acoustic analysis is a tool that provides objective data on changes of speech in dysarthria. Ataxic dysarthria subjects have lower contrast and vowel centralization in carrying out the vowels. The acoustic measures studied in this preliminary work have a high sensitivity in the detection of dysarthria but only the VSA and the mean of primary distances provide information on the severity of this type of speech disturbance.

Using the shared genetics of dystonia and ataxia to unravel their pathogenesis

Esther A.R. Nibbeling, Cathérine C.S. Delnooz, Tom J. de Koning, Richard J. Sinke, Hyder A. Jinnah, Marina A.J. Tijssen, Dineke S. Verbeek, Neuroscience & Biobehavioral Reviews, Available online 28 January 2017, ISSN 0149-7634, doi:10.1016/j.neubiorev.2017.01.033.

In this review we explore the similarities between spinocerebellar ataxias and dystonias, and suggest potentially shared molecular pathways using a gene co-expression network approach. Many patients show a combination of cerebellar ataxia and dystonia. Dystonia is frequently seen in SCA2 (14%), SCA3 (24%) and SCA17 (53%), and regularly seen in SCA types 1, 6, 12, 14, 15/16 and 20, in ataxia telangiectasia, in Friedreich’s ataxia, and in ataxia with oculomotor apraxia. Taken into account the clinical and etiological heterogeneity, the exact pathophysiological mechanisms of SCA and dystonia are not exactly clear. For SCA, several etiological roles have been identified that lead to neurotransmission deficits and result in PC death, including transcriptional dysregulation, autophagy, mitochondrial defects and alterations in calcium homeostasis.In dystonia, the basal ganglia have classically been attributed a key role.

miRNAs as biomarkers of neurodegenerative disorders

Vijitha Viswambharan, Ismail Thanseem, Mahesh M Vasu, Suresh A Poovathinal, and Ayyappan Anitha; Biomarkers in Medicine, February 2017 ,Vol. 11, No. 2 , Pages 151-167 doi: 10.2217/bmm-2016-0242

The potential role of epigenetic changes associated with FRDA including miRNA-based regulatory mechanisms is being studied now. Genetic variations that create miRNA target sites in the 3′-UTR of FXN have been found to affect frataxin expression in FRDA. For example, miRNA-145 has been found to directly bind to the 3′-UTR region of FXN, negatively regulating its expression.

Targeting Class I Histone Deacetylases in a “Complex” Environment

Christopher J. Millard, Peter J. Watson, Louise Fairall, John W.R. Schwabe, Trends in Pharmacological Sciences, Available online 28 January 2017, ISSN 0165-6147, doi:10.1016/j.tips.2016.12.006.

Histone deacetylase (HDAC) inhibitors are proven anticancer therapeutics and have potential in the treatment of many other diseases including HIV infection, Alzheimer’s disease, and Friedreich’s ataxia. A problem with the currently available HDAC inhibitors is that they have limited specificity and target multiple deacetylases. Due to their nonselective nature, many patients experience significant side effects.
The focus within the field is turning to the development of isoform-selective HDAC inhibitors to reduce off-target effects experienced by patients.

New Techniques for Ancient Proteins: Direct Coupling Analysis Applied on Proteins involved in Iron Sulfur Cluster Biogenesis

Marco Fantini, Duccio Malinverni, Paolo De Los Rios, Annalisa Pastore, bioRxiv 103283; doi:10.1101/103283

We have used DCA to analyse three proteins of the iron-sulfur biogenesis machine, an essential metabolic pathway conserved in all organisms. We show that, although based on a relatively small number of sequences due to its distribution in genomes, we can correctly recapitulate all the features of the fold of the CyaY/frataxin family, a protein involved in the human disease Friedreich's ataxia.

Influence of substituent heteroatoms on the cytoprotective properties of pyrimidinol antioxidants

Arnaud Chevalier, Omar M. Khdour, Margaret Schmierer, Indrajit Bandyopadhyay, Sidney M. Hecht, Bioorganic & Medicinal Chemistry, Available online 23 January 2017, ISSN 0968-0896, doi:10.1016/j.bmc.2017.01.030.

Defects in mitochondrial function are linked to numerous neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Friedreich’s ataxia, and are the hallmarks of a number of genetic mitochondrial disorders whose manifestations range from muscle weakness to organ failure. In this context, improvements in mitochondrial function and cellular bioenergetics represent potential targets for therapeutic intervention in mitochondrial diseases.
These compounds are able to quench ROS and lipid peroxidation, maintain mitochondrial membrane potential and confer cytoprotection to cultured cells under conditions of induced oxidative stress. These properties are related to their ability to quench reactive oxygen radicals; therefore, the compounds have been denoted multifunctional radical quenchers (MRQs).
The ability of these compounds to quench lipid peroxidation induced by depletion of glutathione with diethyl maleate (DEM) was evaluated in Friedreich’s ataxia (FRDA) lymphocytes.

Sex Differences in Redox Biology: A Mandatory New Point of View Approaching Human Inflammatory Diseases

Straface Elisabetta, Malorni Walter, and Pietraforte Donatella. Antioxidants & Redox Signaling. January 2017, 26(1): 44-45. doi:10.1089/ars.2016.6931.

Cells from females and males respond differently to chemical and microbial stressors. “Male neurons” are more sensitive to stress induced by oxidants and excitatory neurotransmitters, whereas “female neurons” are more susceptible to some stimuli that prompt apoptosis. The growing interest for the redox medicine in human health has recently suggested a reappraisal of the disease-triggering oxidant-generating enzymes as suitable disease-relevant therapeutic targets. In the light of the reported lines of evidence, a sex- and gender perspective should drive future basic research and pre-clinical studies before starting any pharmacological research aimed at the development of new drugs candidates to counteract redox-related human diseases.

What is quality of life and how do we measure it? Relevance to Parkinson's disease and movement disorders

Pablo Martinez-Martin MD, PhD; Movement Disorders, Version of Record online: 2 DEC 2016 DOI: 10.1002/mds.26885

The objective of this review is to present the conceptual framework, the measures, and some of their most relevant applications in the field of Parkinson's disease and movement disorders. Health-related quality of life is a subjective, individual, and multidimensional construct, and its main dimensions are physical, mental, and social, besides global perceptions of health and personal domains. Health-related quality of life measurement is carried out by means of questionnaires or scales, ideally self-applied by patients, and has a diversity of important applications for clinical practice, research, and health policy.

The origins of the quality of life (QoL) concept are ancient and, in some way, controversial from the beginning. Around 4 centuries before Christ, Greek philosophers proposed the “good life” as a vital goal, an ancestry term of the current notion of QoL. Aristippus (435-350 BC) and the hedonists defended the achievement of pleasure as the basis of happiness, a view later nuanced by Aristotle (384-322 BC), who moved the concept of happiness to the pursuit of activities focused on more worthy objectives and values (eudaimonia: well-being, happiness). The controversy between hedonists and eudaimonics, influenced by new theoretical contributions and inspirations, has in some way continued until the present.

In the setting of movement disorders, it is recommended to increase the number of clinical trials focused on HRQoL, with HRQol acting as the mainendpoint of the study. For obtaining more complete information about HRQoL status and change, a combination of generic and specific measures is recommended. The contents of the generic scales may not be relevant for specific conditions, and their responsiveness may be low; however, the specific instruments can overlook important aspects of general health. For example, in the setting of PD, the SF-36 does not include evaluation of self-image or stigma, whereas the PDQ-39 does not include assessment for energy/fatigue. Finally, for the correct use and interpretation of outcomes, it is advisable to keep in mind the potential limitations that HRQoL instruments, their application, or analysis may present.