Researchers may have uncovered a more effective therapeutic strategy for slowing the progression of Huntington's disease
A research group has shed further light on the mechanisms of Huntington's disease by demonstrating that protein aggregates formed during the disease are a defense mechanism of brain cells that are under stress, not the cause of toxicity, contrary to common belief.
The team, led by Gerardo Lederkremer (Tel Aviv University, Israel), used time-lapse microscopy on tissue cultures of live brain cells from mouse models afflicted with Huntington's disease. They demonstrated that the pathogenic form of the protein huntingtin induces cell stress before its aggregation into visible inclusions. In fact, stress correlated with the presence of huntingtin oligomers and stress slowly subsided upon huntingtin aggregation into inclusions.
“What we found in this study, a surprise, although we suspected it, was that damage to the cells, the cell ‘stress’ that leads to death of cells, appeared well before the protein aggregates did,” said Lederkremer. “Even more surprising, when the aggregates finally appeared, the stress was reduced, in some cases even stopping. The actual process of forming an aggregate was protective, isolating and segregating the problematic proteins. This explains why in autopsies of people who died of Huntington's and other diseases like Alzheimer's or old age, the protein aggregates in the brains were all quite similar, reflecting no specific disease link.”
The majority of individuals diagnosed with Huntington's disease are in their mid-thirties and forties and face complete mental, physical and behavioral decline within two decades. Until now, protein aggregates formed during the progression of the disease have been the main focus of therapies under development. However, these findings might mean that these drugs could in fact be detrimental for therapy of the disease.
“The upsetting implication for therapy of this disease is that drugs being developed to interfere with the formation of protein aggregates may in fact be detrimental,” said Lederkremer. “The identification of the new cause will hopefully lead to the development of new therapeutic approaches. This may hold true for other neurodegenerative diseases as well,” he continued.
These results suggest that interfering with the stress response of brain cells rather than aggregate formation, might be a more effective strategy for slowing the progression of Huntington's disease. This research could pave the way for new pharmaceutical approaches in treating neurodegenerative diseases.
– Written by Evgenia Koutsouki
Sources: Leitman J, Barak B, Benyair R et al. ER stress-induced eIF2-alpha phosphorylation underlies sensitivity of striatal neurons to pathogenic huntingtin. PLoS ONE 9(3), e90803 (2014); Leitman J, Hartl FU, Lederkremer GZ. Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nat. Commun. 4, 2753 (2013).
Scientists from the University of Michigan Comprehensive Cancer Center (MI, USA) have discovered a new way to target prostate cancer, even when it becomes resistant to current anti-hormone treatments. The researchers discovered that the BET bromodomain protein 4 binds to the hormone androgen receptor downstream of where current therapies work.
Senior study author Arul Chinnaiyan, Director of the Michigan Center for Translational Pathology (MI, USA) and SP Hicks, Professor of Pathology at the University of Michigan Medical School (MI, USA), explained, “We think we can target prostate cancer through androgen receptor signaling, rather than directly hitting the androgen receptor. These initial findings suggest the potential that a BET bromodomain inhibitor can work even when prostate cancer becomes resistant to anti-hormone therapies.”
To test the theory in cell lines and mice, JQ1, a compound designed as a BET bromodomain inhibitor was utilized. It was seen that this compound blocked androgen signaling, even in cases of the cells no longer responding to the anti-androgen therapies that are currently used. The inhibitor binds downstream compared with the current treatments, making it potentially unaffected by the resistance. It was also discovered that BET inhibitors are able to block several transcription factors that are known to drive prostate cancer.
Chinnaiyan and study co-author Shaomeng Wang have co-founded a company, called OncoFusion Therapeutics, which will look at developing BET bromodomain inhibitors to attack prostate cancer. Chinnaiyan concludes, “BET bromodomain represents one of the most exciting targets in epigenetics. Developing new ways to treat castration-resistant prostate cancer is critical to improving survival for this disease.”
– Written by Lisa Parks
Sources: Asangani IA, Dommeti V, Wang X et al. Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer. Nature 510(7504), 278–282 (2014); New target for prostate cancer resistant to anti-hormone therapies:www.newswise.com/articles/new-target-for-prostate-cancer-resistant-to-anti-hormone-therapies
A collaborative group has developed a hydrocarbon double-stapled RSV fusion peptide that exhibits promising proteolytic resistance and may be significant in treating respiratory syncytial virus infection (RSV).
RSV accounts for approximately 64 million cases of respiratory disease and 200,000 deaths worldwide each year, yet no broadly effective prophylactic of treatment regimen is currently available.
The team, which was led by Shyam Mohapatra, a scientist at James A Haley Veterans' Hospital (FL, USA), demonstrated that pretreatment with double-stapled RSV peptides, which specifically bound to the RSV fusion bundle, inhibited infection by both laboratory and clinical RSV isolates in cells and murine infection models. In addition, intranasal delivery of a lead double-stapled RSV peptide was found to effectively prevent viral infection of the nares. The group reported that chitosan-based nanoparticle preparation markedly enhanced pulmonary delivery, further preventing progression of RSV infection to the lung.
Speaking to Nanomedicine, Mohapatra commented that, “Increasing the stability of the proposed helical RSV-fusion peptide in vivo using stapling and nanoparticle formulation is key to this prophylaxis.” Mohapatra added that “creating a mucosal cost-effective prophylaxis against RSV infections in babies and the elderly will not only save lives, but also morbidity due to asthma and will save billions of dollars in healthcare costs.”
Mohapatra explained the team's further work: “We are planning to optimize the mucosal nanoparticle formulations, toxicity and PKPD analyses. We are also currently working on identifying partners who may help us take this platform to clinical trials and eventually commercialization.”
– Written by Hannah Coaker
Source: Bird GH, Boyapalle S, Wong T et al. Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection. J. Clin. Invest. 124(5), 2113–2124 (2014).
The US FDA and the EMA are to publish a series of joint question-and-answer documents that outline the conclusions of their first parallel assessment of quality-by-design (QbD) elements of marketing authorization application.
The pilot was launched by the FDA and the EMA in March 2011 in order to communicate review findings regarding QbD elements of applications selected for the program – the ultimate goal of the pilot being to share key findings with the public.
As part of the pilot program, US and European regulators communicate and consult throughout the review process relevant QbD aspects of the new drug and supplement applications. Carrying out a parallel assessment of QbD elements of marketing authorization application is intended to aid sharing of regulatory decisions and facilitate the availability of consistent quality pharmaceutical products throughout the USA and EU.
According to a press release from the FDA, both agencies found the parallel assessment useful and they had been able to reach agreements on a wide range of QbD aspects. At the request of the applicant, experts from the Japanese Pharmaceuticals Medical Devices Agency (Tokyo, Japan) also participated as observers in this first parallel assessment.
– Written by Hannah Coaker
Source: Conclusions of FDA-EMA parallel assessment of quality-by-design elements of marketing applications: www.fda.gov/Drugs/DrugSafety/ucm365524.htm
Researchers from the Wyss Institute at Harvard University (MA, USA) have developed DNA nanoparticles that evade the immune system by acting like a virus and can deliver drugs to tumors.
This approach uses DNA origami, a technique in which DNA is shaped into easily manipulated forms. The team used DNA to mimic the phospholipid coating of a virus in order to evade the immune system and safely deliver nanoparticles to tumors. They programmed the DNA to fold into a small octahedron form and enveloped the DNA nanostructures in PEGylated lipid bilayers that formed a membrane around the particle, a structure that closely resembles a virus. They then injected the nanoparticles coated with fluorescent dye into mice and observed that uncoated nanoparticles were rapidly degraded in contrast with coated nanoparticles, which remained in the bloodstream for hours.
In addition, the team observed that levels of two immune-activating molecules were at least 100-fold lower in mice treated with coated nanodevices as opposed to uncoated nanodevices, indicating an evasion of the immune system by the coated nanoparticles.
“We’re mimicking virus functionality to eventually build therapeutics that specifically target cells,” said senior author William Shih.
These findings could pave the way for developing DNA nanorobots that provide early and accurate diagnosis of cancer, safely deliver drugs to tumors or even produce cancer specific drugs. The same strategy could potentially be used to make protocells, which are microscopic containers that could act as biosensors to detect pathogens in food or toxic chemicals in drinking water.
The team is looking to assemble these DNA shapes into forming DNA microrobots that could sense their environment, calculate how to respond and could even carry out a programmed useful task, such as performing a chemical reaction or generating mechanical force or movement.
– Written by Evgenia Koutsouki
Sources: Perrault DM, Shih WM. Virus-inspired membrane encapsulation of DNA nanostructures to achieve in vivo stability. ACS Nano 8(5), 5132–5140 (2014); Cloaked DNA nanodevices survive pilot mission:http://wyss.harvard.edu/viewpressrelease/150/cloaked-dna-nanodevices-survive-pilot-mission