Xun Ji, Omar M Khdour & Sidney M Hecht; FUTURE MEDICINAL CHEMISTRYVOL. 11, NO. 13; Published Online:30 Aug 2019 doi:10.4155/fmc-2018-0481
Mitochondrial dysfunction is associated with a wide range of human diseases, including neurodegenerative diseases, and is believed to cause or contribute to the etiology of these diseases. These disorders are frequently associated with increased levels of reactive oxygen species. One of the design strategies for therapeutic intervention involves the development of novel small molecules containing redox cores, which can scavenge reactive oxygen radicals and selectively block oxidative damage to the mitochondria. Presently, we describe recent research dealing with multifunctional radical quenchers as antioxidants able to scavenge reactive oxygen radicals. The review encompasses ubiquinone and tocopherol analogs, as well as novel pyri(mi)dinol derivatives, and their ability to function as protective agents in cellular models of mitochondrial diseases.
Monday, September 2, 2019
Sunday, September 1, 2019
The Working Life of People with Degenerative Cerebellar Ataxia
A. Ranavolo, M. Serrao, T. Varrecchia, C. Casali, A. Filla, A. Roca, A. Silvetti, C. Marcotulli, B. M. Rondinone, S. Iavicoli, F. Draicchio; Cerebellum (2019). doi:10.1007/s12311-019-01065-x
Supporting patients with ataxia to find an appropriate job is an important priority because about 78% of non-workers search for a job and workers and non-workers have the same potential work abilities (no relevant differences were found in terms of disease characteristics, gender, and work resilience). In this view, introducing non-workers to work-life may have a potential rehabilitative aspect. Findings of this study highlight that equal job opportunities for subjects affected by cerebellar ataxia are recommended.
Supporting patients with ataxia to find an appropriate job is an important priority because about 78% of non-workers search for a job and workers and non-workers have the same potential work abilities (no relevant differences were found in terms of disease characteristics, gender, and work resilience). In this view, introducing non-workers to work-life may have a potential rehabilitative aspect. Findings of this study highlight that equal job opportunities for subjects affected by cerebellar ataxia are recommended.
Saturday, August 31, 2019
Very-late-onset Friedreich’s ataxia: diagnosis in a kindred with late-onset cerebellar ataxia
Conor Fearon, Roisin Lonergan, Damien Ferguson, Susan Byrne, David Bradley, Yvonne Langan, Janice Redmond; Practical Neurology Published Online First: 29 August 2019. doi: 10.1136/practneurol-2019-002368
Friedreich’s ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25–39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich’s ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich’s ataxia and discuss the pitfalls and risk of misdiagnosis.
Friedreich’s ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25–39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich’s ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich’s ataxia and discuss the pitfalls and risk of misdiagnosis.
Thursday, August 29, 2019
Iron Pathophysiology in Friedreich’s Ataxia
Li K. (2019) Iron Pathophysiology in Friedreich’s Ataxia. In: Chang YZ. (eds) Brain Iron Metabolism and CNS Diseases. Advances in Experimental Medicine and Biology, vol 1173. Springer, Singapore. DOI:10.1007/978-981-13-9589-5_7. Online ISBN: 978-981-13-9589-5
FXN is essential for mitochondrial function by the involvement of iron–sulfur cluster biogenesis. The effects of its deficiency also include disruption of cellular, particularly mitochondrial, iron homeostasis, i.e., relatively more iron accumulated in mitochondria and less iron presented in cytosol. Though iron toxicity is commonly thought to be mediated via Fenton reaction, oxidative stress seems not to be the main problem to result in detrimental effects on cell survival, particularly neuron survival. Therefore, the basic research on FXN function is urgently demanded to understand the disease. This chapter focuses on the outcome of FXN expression, regulation, and function in cellular or animal models of FRDA and on iron pathophysiology in the affected tissues. Finally, therapeutic strategies based on the control of iron toxicity and iron cellular redistribution are considered. The combination of multiple therapeutic targets including iron, oxidative stress, mitochondrial function, and FXN regulation is also proposed.
FXN is essential for mitochondrial function by the involvement of iron–sulfur cluster biogenesis. The effects of its deficiency also include disruption of cellular, particularly mitochondrial, iron homeostasis, i.e., relatively more iron accumulated in mitochondria and less iron presented in cytosol. Though iron toxicity is commonly thought to be mediated via Fenton reaction, oxidative stress seems not to be the main problem to result in detrimental effects on cell survival, particularly neuron survival. Therefore, the basic research on FXN function is urgently demanded to understand the disease. This chapter focuses on the outcome of FXN expression, regulation, and function in cellular or animal models of FRDA and on iron pathophysiology in the affected tissues. Finally, therapeutic strategies based on the control of iron toxicity and iron cellular redistribution are considered. The combination of multiple therapeutic targets including iron, oxidative stress, mitochondrial function, and FXN regulation is also proposed.
Wednesday, August 28, 2019
Oral mobility reflects rate of progression in advanced Friedreich’s ataxia
Borel, S. , Gatignol, P. , Smail, M. , Monin, M. , Ewenczyk, C. , Bouccara, D. and Durr, A. (2019). Ann Clin Transl Neurol. doi:10.1002/acn3.50879
Our objective was to identify a sensitive marker of disease progression in Friedreich’s ataxia. We prospectively evaluated speech, voice, and oromotor function in 40 patients at two timepoints. The mean disease duration was 20.8 ± 9.8 years and mean SARA score 23.7 ± 8.6 at baseline. Oral motor mobility, assessed by a combination of movements of the face, eyes, cheeks, lips, and tongue, decreased significantly after 1 year (P < 0.0001). The standardized response mean over 12 months was considered as large for oral mobility (1.26) but small for SARA (0.12). Oral mobility could therefore be a sensitive marker in therapeutic trials.
Our objective was to identify a sensitive marker of disease progression in Friedreich’s ataxia. We prospectively evaluated speech, voice, and oromotor function in 40 patients at two timepoints. The mean disease duration was 20.8 ± 9.8 years and mean SARA score 23.7 ± 8.6 at baseline. Oral motor mobility, assessed by a combination of movements of the face, eyes, cheeks, lips, and tongue, decreased significantly after 1 year (P < 0.0001). The standardized response mean over 12 months was considered as large for oral mobility (1.26) but small for SARA (0.12). Oral mobility could therefore be a sensitive marker in therapeutic trials.
Friday, August 23, 2019
Application of Quantitative Motor Assessments in Friedreich Ataxia and Evaluation of Their Relation to Clinical Measures
Christian Hohenfeld, Imis Dogan, Robin Schubert, Claire Didszun, Ludger Schöls, Matthis Synofzik, Ilaria A. Giordano, Thomas Klockgether, Jörg B. Schulz, Ralf Reilmann, Kathrin Reetz. Cerebellum (2019). doi:10.1007/s12311-019-01073-x
Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients.
Longitudinal modelling implied minor changes from baseline to follow-up, while clinical scales mainly showed no change in this sample. Overall Q-Motor likely has favourable properties for assessing distinct motor aspects in severe FRDA as it can be administered in wheelchair-bound patients.
Saturday, August 17, 2019
Measuring peripheral nerve involvement in Friedreich’s ataxia
Creigh, P. D., Mountain, J. , Sowden, J. E., Eichinger, K. , Ravina, B. , Larkindale, J. and Herrmann, D. N. (2019). Ann Clin Transl Neurol. doi:10.1002/acn3.50865
MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.
MC density, ENFD, and QST thresholds provide structural and physiologic markers of sensory involvement in FRDA. Longitudinal evaluation is needed to determine whether these measures can identify changes associated with disease progression or treatment.
Exicure, Inc.Announced important preclinical data supporting development of SNA technology in the central nervous system (CNS)
Exicure, Inc. (Nasdaq: XCUR), 8 Aug 2019, pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA™) constructs, today reported financial results for the second quarter ended June 30, 2019 and provided an update on corporate progress.
The first half of 2019 continued to bring advancements across our pipeline,”said Dr. David Giljohann, Exicure’s chief executive officer. “We are extremely pleased with the strong progress in both our neurology and oncology franchises, while we simultaneously strengthened our board leadership and balance sheet. Our non-human primate data confirmed our enthusiasm for neurological applications of our SNA platform. Our recent $63.3 million public offering, which closed on August 2, 2019 provides the financial resources to advance these opportunities,” he added.
Presented results from a biodistribution study of SNAs in the CNS of non-human primates.
SNAs were observed in all 46 regions of the brain examined.
Preclinical research underway in indications including Huntington’s disease, spinocerebellar ataxia type 3 (SCA3), SCA2, SCA1, Friedreich's ataxia and Batten disease.
Expect to nominate first candidate for neurological conditions late in 2019.
The first half of 2019 continued to bring advancements across our pipeline,”said Dr. David Giljohann, Exicure’s chief executive officer. “We are extremely pleased with the strong progress in both our neurology and oncology franchises, while we simultaneously strengthened our board leadership and balance sheet. Our non-human primate data confirmed our enthusiasm for neurological applications of our SNA platform. Our recent $63.3 million public offering, which closed on August 2, 2019 provides the financial resources to advance these opportunities,” he added.
Presented results from a biodistribution study of SNAs in the CNS of non-human primates.
SNAs were observed in all 46 regions of the brain examined.
Preclinical research underway in indications including Huntington’s disease, spinocerebellar ataxia type 3 (SCA3), SCA2, SCA1, Friedreich's ataxia and Batten disease.
Expect to nominate first candidate for neurological conditions late in 2019.
Thursday, August 15, 2019
Mitochondrial disorders and drugs: what every physician should know
Orsucci D, Caldarazzo Ienco E, Siciliano G, Mancuso M.; Drugs in Context 2019; 8: 212588. DOI: 10.7573/dic.212588
In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.
In this review we discuss in an accessible way the therapeutic approaches and perspectives in mitochondrial disorders. We will also provide an overview of the drugs that should be used with caution in these patients.
Wednesday, August 14, 2019
Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development
Natalia Robledinos-Antón, Raquel Fernández-Ginés, Gina Manda, and Antonio Cuadrado, Oxidative Medicine and Cellular Longevity, vol. 2019, Article ID 9372182, 20 pages, 2019. doi:10.1155/2019/9372182.
Synthetic triterpenoids have been derived from the natural compound oleanolic acid to provide them with strong Michael acceptor reactivity. This is achieved mainly through the addition of enone and ciano groups to the A ring and another enone group to the C ring. Bardoxolone methyl (CDDO-Me or RTA 402) reached clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes mellitus. Although phase II clinical trials demonstrated long-term increment in glomerular filtration, CDDO-Me was halted at phase III due to cardiovascular safety issues. A new phase II clinical trial has recently started recruiting patients with rare chronic kidney diseases to better define the safety and efficacy profiles of CDDO-Me. Currently, CDDO-Me is also under clinical study for the Alport syndrome and pulmonary hypertension. In an effort to improve the safety profile, a second-generation difluoromethyl acetamide derivative of bardoxolone methyl, called RTA-408 (Omaveloxone), is now under clinical investigation in phase II clinical trials for Friedreich’s ataxia, ocular inflammation, and pain after ocular surgery [50]. Recently, a preclinical study evaluated RTA-408 for diabetic wound recovery and pointed NRF2 upregulation as responsible for the observed improvement in regenerative capacity.
Synthetic triterpenoids have been derived from the natural compound oleanolic acid to provide them with strong Michael acceptor reactivity. This is achieved mainly through the addition of enone and ciano groups to the A ring and another enone group to the C ring. Bardoxolone methyl (CDDO-Me or RTA 402) reached clinical trials for the treatment of advanced chronic kidney disease (CKD) and type 2 diabetes mellitus. Although phase II clinical trials demonstrated long-term increment in glomerular filtration, CDDO-Me was halted at phase III due to cardiovascular safety issues. A new phase II clinical trial has recently started recruiting patients with rare chronic kidney diseases to better define the safety and efficacy profiles of CDDO-Me. Currently, CDDO-Me is also under clinical study for the Alport syndrome and pulmonary hypertension. In an effort to improve the safety profile, a second-generation difluoromethyl acetamide derivative of bardoxolone methyl, called RTA-408 (Omaveloxone), is now under clinical investigation in phase II clinical trials for Friedreich’s ataxia, ocular inflammation, and pain after ocular surgery [50]. Recently, a preclinical study evaluated RTA-408 for diabetic wound recovery and pointed NRF2 upregulation as responsible for the observed improvement in regenerative capacity.
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