Emerging therapies for mitochondrial disorder

Helen Nightingale, Gerald Pfeffer, David Bargiela, Rita Horvath, Patrick F. Chinnery. Brain, 1633-1648 First published online: 3 May 2016 DOI:10.1093/brain/aww081

Open Access, (Creative Commons Attribution License)

From a clinical perspective, nuclear-genetic enzyme defects show the greatest promise. Stem cell therapy is already being used in specific contexts, and its efficacy and safety being evaluated, and gene therapy trials in mouse models show clear benefits. Unfortunately, each one of these rare genetic diseases may require their own proprietary approach, and the impact needs to be evaluated long-term. Small molecules are attractive because they have the potential to provide a more generic solution applicable across the mitochondrial disease spectrum, and a greater understanding of cell signalling pathways opens up several unexpected disease targets. For some of these drugs, clinical evaluation is imminent, particularly for those being repurposed or repositioned drugs such as bezafibrate. It is critical at this stage that laboratory and clinical scientists work closely with patient organizations to ensure that the ultimate aims of therapy will actually tackle issues that are important to patients. Given limited resources, this will ensure that new treatments improve quality of life—a prerequisite if these treatments are going to be adopted by healthcare systems worldwide.

Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases

Mirjam Plantinga, Erwin Birnie, Kristin M Abbott, Richard J Sinke, Anneke M Lucassen, Juliette Schuurmans, Seyma Kaplan, Marian A Verkerk, Adelita V Ranchor and Irene M van Langen; European Journal of Human Genetics (2016) 24, 1417–1423; doi:10.1038/ejhg.2016.43

OPEN ACCESS

‘You should at least ask’. The expectations, hopes and fears of rare disease patients on large-scale data and biomaterial sharing for genomics research

Pauline McCormack, Anna Kole, Sabina Gainotti, Deborah Mascalzoni, Caron Molster, Hanns Lochmüller and Simon Woods; European Journal of Human Genetics (2016) 24, 1403–1408; doi:10.1038/ejhg.2016.30

One of the means of doing this is to ensure that patient organisations are represented in ongoing governance of a global platform such as RD-Connect as part of ensuring that participants feel they have an equivalent level of protection and control in these global interactions as they do in their local relationships with researchers.

Longitudinal study of gait lower limb coordination and rehabilitative indications in patients affected by Ataxia of Friedreich (FRDA)

M. Petrarca, G. Vasco, S. Gazzellini, S. Carniel, A. Pisano, E. Bertini, E. Castelli, Gait & Posture, Volume 49, Supplement 1, September 2016, Pages S2-S3, ISSN 0966-6362, doi:10.1016/j.gaitpost.2016.07.025.

The resulting walking pattern is the product of a complex interaction between cerebellar dysfunction and sensory loss,compromising both balance control and multi-joint coordination. It is possible to speculate on the reduction of sensibility and of selective muscular control which produces increased exploitation of the body biomechanical properties.

Breast cancer tumorigenicity is dependent on high expression levels of NAF-1 and the lability of its Fe-S clusters

Merav Darash-Yahanaa, Yair Pozniakb, Mingyang Luc, Yang-Sung Sohn, Ola Karmi, Sagi Tamir, Fang Bai, Luhua Song, Patricia A. Jennings, Eli Pikarsky, Tamar Geiger, José N. Onuchic, Ron Mittler and Rachel Nechushtai, PNAS early/2016/09/07, DOI:10.1073/pnas.1612736113

Freely available online through the PNAS open access option.

Disrupted expression of frataxin, another protein involved in Fe-S biogenesis, in hepatocytes of transgenic mice similarly led to impaired mitochondrial function, oxidative stress, and the development of multiple hepatic tumors. Moreover, ISCU and frataxin are regulated at the transcriptional level by p53 controlling the levels of ROS in cells

Retrotope Announces Phase I/II Clinical Trial Results of RT001 in Treatment of Friedreich's Ataxia

LOS ALTOS, CA--(Marketwired - Sep 16, 2016) - Dr. Theresa Zesiewicz, principal investigator in Retrotope's first-in-human clinical trial of RT001 in Friedreich's ataxia (FA), today presented early results from Retrotope's Phase I/II trial conducted at the University of South Florida Ataxia Research Center and the Collaborative NeuroSciences Network in Long Beach, CA. The trial, a randomized, double-blind, comparator controlled, two-dose study of RT001 in 18 FA patients for 28 days, met all of its primary safety, tolerability and pharmacokinetic (PK) goals. While biological activity was not a primary goal of the study, a number of clinically important activity measures were tested, found to be highly correlated to well-studied disease severity scales and showed multiple, unexpected, robust signals of drug effect at one or more doses.

Characterization of human mitochondrial ferritin promoter: identification of transcription factors and evidences of epigenetic control

Michela Guaraldo, Paolo Santambrogio, Elisabetta Rovelli, Augusta Di Savino, Giuseppe Saglio, Davide Cittaro, Antonella Roetto & Sonia Levi; Scientific Reports 6, Article number: 33432 (2016) doi:10.1038/srep33432

The reagents Aza and NaB make the DNA accessible to transcription factors and activate FTMT expression. Our findings sustain that the moderate induction of FTMT expression by epigenetic therapy could be useful in disease characterized by oxidative stress, as FRDA.

UF and the Advocacy Group GoFAR Announce Gene Therapy program for Friedreich’s Ataxia

Press release: Gainesville - FL, Torino - IT, Sept.13, 2016

USF Health and FARA to host patient-focused scientific symposium Sept. 15

USF Health and FARA to host patient-focused scientific symposium Sept. 15 [Video], Written by Anne DeLotto Baier · September 12, 2016

International experts from academia and industry will gather to discuss advances in Friedreich’s ataxia from the laboratory to the clinic.

 Tampa, FL (Sept. 12, 2016) — The University of South Florida (USF) will bring together leading researchers and patients searching for a treatment for Friedreich’s ataxia (FA) and related disorders at the eighth annual scientific symposium “Understanding Energy for A Cure.” The symposium will be held 5 to 8:30 p.m., Thursday, Sept. 15, at the USF Sam and Martha Gibbons Alumni Center, 11810 USF Alumni Drive, Tampa, FL 33620.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

Maya Kuperberg, Dorit Lev, Lubov Blumkin, Ayelet Zerem, Mira Ginsberg, Ilan Linder, Nirit Carmi, Sarah Kivity, Tally Lerman-Sagie, Esther Leshinsky-Silver; August 29, 2016, doi: 10.1177/0883073816664836

When a patient arrives with a suspected monogenic disease the authors first take detailed history, perform a full clinical exam, and create a family tree. If a specific genetic disease is suspected based on this data, direct traditional tests are to be performed. Only if the patient remains undiagnosed should the authors turn to whole exome sequencing. The authors were able to diagnose patients exhibiting nonspecific, atypical, or overlapping symptoms.

Over 300 genetic conditions are known to cause ataxia, and without additional specific symptoms achieving a diagnosis is very difficult. Whole exome sequencing studies on cerebellar ataxia have achieved a success rate of 18%-64%. The authors report a high success rate of 57.1% for patients with ataxia.