Computational drug repositioning for rare diseases in the era of precision medicine

Brian Delavan, Ruth Roberts, Ruili Huang, Wenjun Bao, Weida Tong, Zhichao Liu, Drug Discovery Today, 2017, , ISSN 1359-6446, doi:10.1016/j.drudis.2017.10.009.

There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases. First, we summarize the current genome landscape of rare diseases. Second, we propose several promising bioinformatics approaches and pipelines for computational drug repositioning for rare diseases. Finally, we discuss recent regulatory incentives and other enablers in rare disease drug development and outline the remaining challenges.

Depressive symptoms in Friedreich ataxia

Antonieta Nieto, Atteneri Hernández-Torres, Javier Pérez-Flores, Fernando Montón, International Journal of Clinical and Health Psychology, Available online 8 December 2017, ISSN 1697-2600, doi:10.1016/j.ijchp.2017.11.004.

Almost no attention has been paid to depression in Friedreich ataxia (FRDA), a highly disabling cerebellar degenerative disease. Our aim was to study the presence and the profile of depressive symptoms in FRDA and their relationship with demographic-disease variables and cognitive processing speed. Method: The study groups consisted of 57 patients with a diagnosis of FRDA. The Beck Depression Inventory-II was used to assess symptoms of depression. Speed of information processing was measured with a Choice Reaction time task. The mean BDI score for patients was significantly higher than the mean score in the general population. Twenty one percent of participants scored in the moderate/severe range. A Cognitive-Affective score and a Somatic-Motivational score was calculated for each patient. Patients’ scores in both dimensions were significantly higher than the scores in the general population. Demographic and disease variables were not related with symptoms of depression, except for severity of ataxia. Depressive symptoms predict cognitive reaction times. The greater proportion of variance was explained by the Cognitive-Affective dimension. Our data show that both somatic-motivational and cognitive affective symptoms of depression are frequent in individuals with FRDA. In addition, depressive symptoms may influence cognition, especially, the cognitive and affective symptoms.

Mitochondrial pore opening and loss of Ca2 + exchanger NCLX levels occur after frataxin depletion

R. Purroy, E. Britti, F. Delaspre, J. Tamarit, J. Ros, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Available online 6 December 2017, ISSN 0925-4439, doi:10.1016/j.bbadis.2017.12.005.

Frataxin-deficient neonatal rat cardiomyocytes and dorsal root ganglia neurons have been used as cell models of Friedreich ataxia. In previous work we show that frataxin depletion resulted in mitochondrial swelling and lipid droplet accumulation in cardiomyocytes, and compromised DRG neurons survival. Now, we show that these cells display reduced levels of the mitochondrial calcium transporter NCLX that can be restored by calcium-chelating agents and by external addition of frataxin fused to TAT peptide. Also, the transcription factor NFAT3, involved in cardiac hypertrophy and apoptosis, becomes activated by dephosphorylation in both cardiomyocytes and DRG neurons. In cardiomyocytes, frataxin depletion also results in mitochondrial permeability transition pore opening. Since the pore opening can be inhibited by cyclosporin A, we show that this treatment reduces lipid droplets and mitochondrial swelling in cardiomyocytes, restores DRG neuron survival and inhibits NFAT dephosphorylation. These results highlight the importance of calcium homeostasis and that targeting mitochondrial pore by repurposing cyclosporin A, could be envisaged as a new strategy to treat the disease.

Friedreich ataxia: Clinical feature and electrophysiological symptoms

Oguri M. ; J Neurosci Rural Pract [serial online] 2017 [cited 2017 Dec 6];8:691-2. DOI: 10.4103/jnrp.jnrp_248_17

The ataxia is slowly progressive and involves the lower extremities to a greater degree than the upper extremities. In general, results of electrophysiologic studies including visual, auditory brainstem, and somatosensory-evoked potentials are often abnormal.

Iron-induced oligomerization of human FXN 81-210 and bacterial CyaY frataxin and the effect of iron chelators

Eva-Christina Ahlgren, Mostafa Fekry, Mathias Wiemann, Christopher A. Söderberg, Katja Bernfur, Olex Gakh, Morten Rasmussen, Peter Højrup, Cecilia Emanuelsson, Grazia Isaya, Salam Al-Karadaghi. PLoS ONE 12(12): e0188937. doi:10.1371/journal.pone.0188937

Patients suffering from the progressive neurodegenerative disease Friedreich’s ataxia have reduced expression levels of the protein frataxin. Three major isoforms of human frataxin have been identified, FXN42-210, FXN56-210 and FXN81-210, of which FXN81-210 is considered to be the mature form.

C-Path And FARA Announce Collaborative Data Aggregation Project For Friedreich’s Ataxia

Tucson, AZ, and Downingtown, PA — Dec. 4, 2017 — Critical Path Institute's (C-Path) Data Collaboration Center (DCC) and the Friedreich's Ataxia Research Alliance (FARA) have announced that they will work together to develop an aggregated database of clinical data for Friedreich's ataxia (FA). Use of this database will promote collaborative research to support the understanding of natural history, potential biomarkers, and potential clinical endpoints for patients with FA, which will help researchers develop more efficient clinical trial protocols to test new therapies more quickly and effectively.

The project will establish an integrated database of clinical data for FA that can be shared and utilized by existing FA researchers. It will enlist companies that have carried out clinical trials in FA to obtain contributions of clinical data, as well as sharing natural history data collected by FARA's collaborative clinical research network.

The role of oxidative stress in Friedreich's ataxia

Federica Lupoli, Tommaso Vannocci, Giovanni Longo, Neri Niccolai and Annalisa Pastore. FEBS Letters, DOI: 10.1002/1873-3468.12928

Friedreich's ataxia is an excellent paradigmatic example of a disease in which oxidative stress plays an important, albeit not completely understood, role. Friedreich's ataxia is a rare genetic neurodegenerative disease which involves partial silencing of frataxin, a small mitochondrial protein completely ignored before being linked to Friedreich's ataxia.

Peripheral nerve ultrasound in Friedreich ataxia

Mulroy, E., Pelosi, L., Leadbetter, R., Joshi, P., Rodrigues, M., Mossman, S., Kilfoyle, D. and Roxburgh, R. (2017). Muscle Nerve. doi: 10.1002/mus.26012

The nerves of the patients with FRDA were significantly larger than those of healthy controls at all upper limb sites (P < 0.05) but not significantly different in the lower limbs.
Our findings add additional weight to the theory that dorsal root ganglionopathy is not the sole cause of peripheral sensory loss in FRDA. Peripheral neuropathic processes are also likely to play a role.

Synthetic transcription elongation factors license transcription across repressive chromatin

Graham S. Erwin, Matthew P. Grieshop, Asfa Ali, Jun Qi, Matthew Lawlor, Deepak Kumar, Istaq Ahmad, Anna McNally, Natalia Teider, Katie Worringer, Rajeev Sivasankaran, Deeba N. Syed, Asuka Eguchi, Md. Ashraf, Justin Jeffery, Mousheng Xu, Paul M. C. Park, Hasan Mukhtar, Achal K. Srivastava, Mohammed Faruq, James E. Bradner, Aseem Z. Ansari; Science 30 Nov 2017 eaan6414, Published Online 30 Nov 2017 DOI: 10.1126/science.aan6414

The molecule being tested is designed to assist the enzyme that reads, or “transcribes,” DNA at the confusing repeats. Once it reaches the other side, the enzyme, called RNA polymerase, reads the gene and makes RNA that in turn codes for frataxin, the protein that is lacking in Friedreich’s ataxia.

Designer molecule points to treatment for diseases caused by DNA repeats

University of Wisconsin–Madison news, November 30, 2017 By David Tenenbaum.


Using a molecule designed to overcome a roadblock formed by a common type of genetic flaw, researchers at the University of Wisconsin–Madison have made progress towards novel molecular treatments for Friedreich’s ataxia — a rare but fatal disorder — in the laboratory dish and in animals.