Synthetic genome readers target clustered binding sites across diverse chromatin states

Graham S. Erwin, Matthew P. Grieshop, Devesh Bhimsaria, Truman J. Do, José A. Rodríguez-Martínez, Charu Mehta, Kanika Khanna, Scott A. Swanson, Ron Stewart, James A. Thomson, Parameswaran Ramanathan, and Aseem Z. Ansari; PNAS 2016 113 (47) E7418-E7427; published ahead of print November 8, 2016, doi: 10.1073/pnas.1604847113

The linear polyamide (3) studied here was designed to bind to GAA repeats in the first intron of frataxin, a locus that appears to be situated within heterochromatin marked by H3K9me3. Taken together, the ability of polyamides to access heterochromatin (a major barrier to binding to natural and artificial DNA-binding factors) opens unique opportunities to deploy this class of synthetic genome readers to regulate gene networks that direct cellular fate and function. Linear 3, designed to target 5′-AAGAAGAAG-3′, is designed to target a GAA repeat expansion found in patients with Friedreich’s ataxia to alleviate transcriptional repression.
The COSMIC-seq approach that we describe here is a robust and broadly applicable method that can be readily extended to map the genome-wide binding properties of other classes of DNAbinding molecules, including several genome-directed therapeutics. COSMIC-seq will be instrumental in the genome-guided design of molecules that serve as precision-targeted therapeutics.

A wearable proprioceptive stabilizer for rehabilitation of limb and gait ataxia in hereditary cerebellar ataxias: a pilot open-labeled study

Luca Leonardi, Maria Gabriella Aceto, Christian Marcotulli, Giuseppe Arcuria, Mariano Serrao, Francesco Pierelli, Paolo Paone, Alessandro Filla, Alessandro Roca, Carlo Casali. Neurol Sci (2016). First Online: 31 December 2016 doi:10.1007/s10072-016-2800-x

The aim of this pilot study is to test the feasibility and effectiveness of a wearable proprioceptive stabilizer that emits focal mechanical vibrations in patients affected by hereditary cerebellar ataxias. This small open-labeled study shows preliminary evidence that focal mechanical vibration exerted by a wearable proprioceptive stabilizer might improve limb and gait ataxia in patients affected by hereditary cerebellar ataxias.

CN Project OPUS10: “Role of microRNAs in regulation iron metabolism in Friedreich's ataxia”

biotechnologia.pl; Prof. Włodzimierz Krzyżosiak, Institute of Bioorganic Chemistry PAS, Polish Academy of Sciences.(2017-01-02)

The goals of this project are to define changes in the expression and activity of microRNAs in FRDA, and analyze how these abnormalities affect the activity of genes which are responsible for the localization and amount of iron in neuronal and heart cells of patients with Friedreich’s ataxia. We will define relationship between miRNA molecules and iron availability. We will also uncover the pattern of detectable microRNA molecules that is specific to FRDA.

Percutaneous needle tenotomy for the treatment of muscle and tendon contractures in adults with brain damage: results and complications

Flavia Coroian, Claire Jourdan, Jérome Froger, Claire Anquetil, Olivier Choquet, Bertand Coulet, Isabelle Laffont, Archives of Physical Medicine and Rehabilitation, Available online 18 December 2016, ISSN 0003-9993, doi:10.1016/j.apmr.2016.11.014.

In our series, percutaneous needle tenotomy procedures under local or locoregional anesthesia were performed by a PM&R physician trained by an orthopedic surgeon and yielded very few complications. This technique seems relevant for contractures of several superficial tendons for the upper and lower limb alike. Furthermore, this technique gives a satisfactory orthopedic outcome fulfilling non-functional objectives (hygiene, pain, nursing) and even functional ones for a small number of well-selected patients (gait, grip, daily life).
PNT yields good results in the management of superficial muscle and tendon contractures in selected brain-damaged patients. The complications rate is very low and this treatment can be an alternative to conventional surgery in frail neurological patients.

Gene therapy: Gene-editing therapy for neurological disease

Moira A. McMahon & Don W. Cleveland. Nature Reviews Neurology 13, 7–9 (2017) doi:10.1038/nrneurol.2016.190 Published online 16 December 2016.

Guide RNA-mediated CRISPR–Cas nucleases are a powerful technology for the engineering of mammalian genomes. CRISPR–Cas9-dependent editing of mutated genes that cause Huntington disease and fragile X syndrome was recently achieved in cell-based models, heralding the first step towards developing this technology into viable therapeutics for neurological diseases.
The successful translation of these proof‑of‑principle studies to in vivo gene editing is eagerly anticipated, but several challenges remain. One major challenge is delivery of the sgRNA and nuclease to target cells. A final major challenge for extension of gene-editing approaches to applications within the nervous system is the efficiency of gene silencing or correction: can the changes be made in sufficient numbers of cells to alter the disease course?.
What seems certain is that continued development of genome-editing technology to target neurological diseases is likely to provide a greater understanding of the diseases themselves and, hopefully, will one day form the basis of a successful therapy.

Clinical trials: To catch a crook, you might try statistics

Gary R. Cutter; Nature Reviews Neurology 13, 9–10 (2017) doi:10.1038/nrneurol.2016.194 Published online 16 December 2016

To reduce research fraud, we need to understand more deeply why professional researchers and clinicians commit fraud. Certainly, personal interest is a major factor. Review boards thoroughly assess conflicts of interest to protect authors from gaining excess monetary gains via publications, but we have little to protect against advancing one’s personal interests — indeed, we reward it. Promotions, grants and grant renewals all depend on publications. Moreover, researchers might commit fraud for more egotistic reasons than mere survival in their chosen career, such as for money or to get a product on the market, to boost the market value of their start‑up company, or perhaps even to deliberately sabotage competitors.
Making trial and other experimental data publicly available have been suggested as one
strategy to reduce fraud, as any interested individual could search for evidence, thereby making fraud less tempting. However, the consequences of the false positives should be kept in mind: do we wish to impugn even one honest researcher in our attempts to catch dishonest ones?.

Single Protein May Hold Secret to Treating Parkinson’s Disease and More

By Dana G. Smith, PhD / Gladstone News / December 26, 2016.

“Nrf2 coordinates a whole program of gene expression, but we didn’t know how important it was for regulating protein levels until now,” explained first author Gaia Skibinski, PhD, a staff research scientist at Gladstone. “Overexpressing Nrf2 in cellular models of Parkinson’s disease resulted in a huge effect. In fact, it protects cells against the disease better than anything else we’ve found.”

The scientists say that Nrf2 itself may be difficult to target with a drug because it is involved in so many cellular processes, so they are now focusing on some of its downstream effects. They hope to identify other players in the protein regulation pathway that interact with Nrf2 to improve cell health and that may be easier to drug.

Synthetic genome readers target clustered binding sites across diverse chromatin states

Graham S. Erwin, Matthew P. Grieshop, Devesh Bhimsaria, Truman J. Do, José A. Rodríguez-Martínez, Charu Mehta, Kanika Khanna, Scott A. Swanson, Ron Stewart, James A. Thomson, Parameswaran Ramanathan, and Aseem Z. Ansari, PNAS 2016 ; published ahead of print November 8, 2016, doi: 10.1073/pnas.1604847113

Nucleosomal DNA, even in heterochromatin, may thus be partially preorganized to accommodate polyamide binding in the minor groove. The linear polyamide (3) studied here was designed to bind to GAA repeats in the first intron of frataxin to alleviate transcriptional repression, a locus that appears to be situated within heterochromatin marked by H3K9me3. Taken together, the ability of polyamides to access heterochromatin (a major barrier to binding to natural and artificial DNA-binding factors) opens unique opportunities to deploy this class of synthetic genome readers to regulate gene networks that direct cellular fate and function.

Correction of the frataxin gene using CRISPR

Deletion of the GAA repeats from the human frataxin gene using the CRISPR-Cas9 system in YG8R-derived cells and mouse models of Friedreich Ataxia. D L Ouellet, K Cherif, J Rousseau and J-P Tremblay; Gene Therapy, accepted article preview 26 December 2016; doi: 10.1038/gt.2016.89.

Short title: Correction of the frataxin gene using CRISPR

Here, we use the CRISPR-Cas9 system to remove the mutated GAA expansion and restore the frataxin gene transcriptional activity and protein level. Both YG8R and YG8sR mouse models and cell lines derived from these mice were used to CRISPR-edited successfully the GAA expansion in vitro and in vivo.
All experiments present in this article help to identify the most suitable mouse model for gene editing in vivo, hoping this will quickly lead to human clinical trials in Friedreich ataxia patients. However, as any kind of therapy, the side effects of a treatment must be clearly defined and known before going further with the massive treatment of patients.

DNA repair in the trinucleotide repeat disorders

Lesley Jones, Henry Houlden, Sarah J Tabrizi; The Lancet Neurology, Volume 16, Issue 1, January 2017, Pages 88-96, ISSN 1474-4422, doi:10.1016/S1474-4422(16)30350-7


Some pathogenic mechanisms are common to multiple diseases. For instance, a repeat that prevents gene expression is seen in fragile X syndrome and Friedreich’s ataxia. Mechanisms related to DNA repair have been implicated as modulators of somatic expansion of the disease-associated repeated sequences in mouse modelsof Huntington’s disease, myotonic dystrophy, fragile X syndrome, and Friedreich’s ataxia.

Where next?: To understand the common genetic architecture of trinucleotide repeat disorders and any further genetic susceptibilities in individual disorders, genetic analysis with increased numbers of variants and sample sizes is needed, followed by sequencing approaches to define the phenotype-modifying variants. The findings must then be translated into cell biology analyses to elucidate the mechanisms through which the genetic variants operate. Genes that have roles in the DNA damage response could underpin a common DNA repeat-based mechanism and provide new therapeutic targets (and hence therapeutics) in multiple trinucleotide repeat disorders.