Wednesday, February 22, 2017

E3 Ligase RNF126 Directly Ubiquitinates Frataxin, Promoting Its Degradation: Identification of a Potential Therapeutic Target for Friedreich Ataxia

Monica Benini, Silvia Fortuni, Ivano Condò, Giulia Alfedi, Florence Malisan, Nicola Toschi, Dario Serio, Damiano Sergio Massaro, Gaetano Arcuri, Roberto Testi, Alessandra Rufini, Cell Reports, Volume 18, Issue 8, 21 February 2017, Pages 2007-2017, ISSN 2211-1247, doi: 10.1016/j.celrep.2017.01.079.

RNF126 depletion results in frataxin accumulation in cells derived from FRDA patients, highlighting the relevance of RNF126 as a new therapeutic target for Friedreich ataxia.
A combined therapy aimed at increasing frataxin levels, either by promoting its gene transcription or through gene therapy or protein replacement, and simultaneously interfering with its RNF126-mediated degradation could be envisioned.

Thursday, February 16, 2017

A study of CTI-1601 for the treatment of Friedreich's Ataxia.

Adis International Ltd. Part of Springer Science+Business Media, Trials

Phase of Trial: Phase I
Latest Information Update: 14 Feb 2017

06 Feb 2017: According to a Chondrial Therapeutics media release, company is planning to file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) and after acceptance of the IND, company will initiate this trial.

Tuesday, February 14, 2017

Health technology assessment of drugs for rare diseases: insights, trends, and reasons for negative recommendations from the CADTH common drug review

Ghayath Janoudi, William Amegatse, Brendan McIntosh, Chander Sehgal, and Trevor Richter; Orphanet J Rare Dis. 2016; 11: 164. doi:10.1186/s13023-016-0539-3

A shift in biochemical research towards drugs for rare diseases has created new challenges for the pharmaceutical industry, government regulators, health technology assessment agencies, and public and private payers. In this article, we aim to comprehensively review, characterize, identify possible trends, and explore reasons for negative reimbursement recommendations in submissions made to the Common Drug Review (CDR) for drugs for rare diseases (DRD) at the Canadian Agency for Drugs and Technologies in Health (CADTH), a publicly funded pan-Canadian health technology assessment agency.
From 2004 to 2015, 63 of 434 submissions to the CDR were for DRD (range: 1 submission in 2005 to 10 submissions in 2013). Most (74.6%) submissions included at least one double-blind randomized controlled trial (RCT). The average study size was 190 patients (range: 20 to 742). The average annual treatment cost was C$215,631 (range: $9,706 to $940,084). Reimbursement recommendations were positive for 54% of the submissions. Negative reimbursement recommendations were made due to a lack of clinical effectiveness (38.5%), insufficient evidence (30.8%), multiple reasons (23.1%), or lack of cost effectiveness/high cost (7.7%).
The number of DRD submissions to CDR increased since 2013; from 4 to 5 per year between 2004 and 2012, to 10, 9, and 8 in 2013, 2014, and 2015 respectively. More than half of DRD submissions received positive reimbursement recommendation. Poor quality evidence and/or lack of supportive clinical evidence was at least partly responsible for a negative reimbursement recommendation in all cases. Although the average cost of DRD treatments was high, high cost was a reason for a negative reimbursement recommendation in only two (7.7%) of negative reimbursement recommendations.

Saturday, February 11, 2017

Industrializing rare disease therapy discovery and development

Sean Ekins; Nature Biotechnology 35, 117–118 (2017) doi:10.1038/nbt.3787 Published online 08 February 2017

There would also need to be close interactions between these scientists, clinicians, rare disease patients, and their families and the many rare disease foundations that could perhaps help fund uch a concentrated effort. To build the scale that could handle orders of magnitude more diseases would require the use of computational, automation, and informatics tools to help identify, create, and manufacture treatments and facilitate the collaborations necessary to create a pipeline to bring them to the clinic. Centralizing efforts on rare diseases would also need to bring with it the relevant expertise necessary to go from the preclinical to clinical stages. Treatment discovery in the pharmaceutical and biotech industry has been suggested as needing disruption. Industrialization of rare disease treatment development may lead the way to a more sustainable future that will have considerable support if it ultimately drives down the cost of rare disease treatments.

Friday, February 10, 2017

Mitochondria-penetrating peptides conjugated to desferrioxamine as chelators for mitochondrial labile iron

Alta RYP, Vitorino HA, Goswami D, Liria CW, Wisnovsky SP, Kelley SO, Machini MT, Espósito BP. (2017). PLoS ONE 12(2): e0171729. doi:10.1371/journal.pone.0171729

Diseases such as hereditary hemochromatosis or thalassemia are characterized by non-localized deposits of excess iron, however a number of conditions are known in which iron overload is circumscribed to a specific tissue or organelle (neurodegeneration with brain iron accumulation, hereditary X-linked sideroblastic anemia, anemia of chronic disease. Patients of FA typically have a decreased expression of the peptide frataxin, which assists the assembly of iron-sulfur clusters within the mitochondria.
In conclusion, the production of mtDFO is an interesting strategy to load a powerful, yet impermeant siderophore into either cytoplasm or mitochondria. This could contribute to the improvement of several iron overload conditions, where iron excess is either systemic or localized into specific tissues/organelles. Results indicate that mtDFO could be promising compounds for amelioration of the disease symptoms of iron overload in mitochondria.

Thursday, February 9, 2017

Shire divests mRNA platform to RaNa

Nature Biotechnology 35,103 (2017) doi:10.1038/nbt0217-103b Published online 08 February 2017

The Shire deal includes preclinical drug programs in cystic fibrosis and urea cycle disorders to augment RaNa’s pipeline. In 2015, RaNa raised $55 million in venture capital to continue development of epigenetic gene upregulation and mRNA stabilization technologies and support the company’s programs in spinal muscular dystrophy and Friedreich’s ataxia.

Wednesday, February 8, 2017

Comparison of Two Different PCR-based Methods for Detection of GAA Expansions in Frataxin Gene

Mona ENTEZA­M, Akbar AMIRFIROOZI, Mansoureh TOGHA, Mohammad KERAMATIPOUR; Iranian Journal of Public Health 2017. 46(2):222-228.

The presence or absence of expanded alleles can be identified correctly by TP-PCR. Performing long-PCR and Fluorescent-long-PCR enables accurate genotyping in all samples. This approach is highly reliable. It could be successfully used for detection of GAA expansion repeats.

Tuesday, February 7, 2017

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.

Friday, February 3, 2017

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.

Thursday, February 2, 2017

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.