Showing posts sorted by date for query appeal from the. Sort by relevance Show all posts
Showing posts sorted by date for query appeal from the. Sort by relevance Show all posts

Saturday, April 11, 2020

Study first to show pharmacological chaperone therapy prevents Alzheimer's in mice

Like pieces of tape that crumple, stick together, and can be turned into a ball, proteins that begin to lose their shape become sticky and tend to clump together. When this happens, rather than being transported to recycling sites within cells, old or dysfunctional proteins instead become trapped within cellular compartments. Eventually, they accumulate to the point that they gum up cellular machinery, causing major problems.

Fortunately, cells are equipped with molecular machinery that detects defective proteins, sorts them out, and then either removes or stabilizes them, preventing them from accumulating and causing harm. In recent years, scientists have developed small drug molecules, known as pharmacological chaperones, that can help in this process.
Now, scientists at the Lewis Katz School of Medicine at Temple University show that pharmacological chaperones could fill a critical role in Alzheimer's disease therapy. In a new study published online January 21 in the journal Molecular Neurodegeneration, they describe a novel pharmacological chaperone capable of preventing Alzheimer's disease in animals prone to developing the condition.
The study is the first to show that a pharmacological chaperone drug can effectively disrupt the abnormal processes that damage neurons in the brain, fuel memory loss, and ultimately give rise to Alzheimer's disease.
"Our chaperone drug specifically restored levels of a sorting molecule known as VPS35, which helps move proteins out of endosomes, compartments inside cells where proteins are sorted for degradation," explained Domenico Praticò, MD, the Scott Richards North Star Charitable Foundation Chair for Alzheimer's Research, Professor in the Departments of Pharmacology and Microbiology, and Director of the Alzheimer's Center at Temple in the Lewis Katz School of Medicine. Dr. Praticò was a senior investigator on the new study.
The trafficking of proteins from endosomes to the cell membrane or to another cellular compartment known as the Golgi apparatus is fundamental for normal cell function. VPS35 is of particular importance to this trafficking system since it separates out dysfunctional and old proteins and sends them off for recycling.
In previous work, Dr. Praticò and colleagues found that VPS35 actively clears the brain of potentially harmful proteins such as amyloid-beta and tau. However, in Alzheimer's disease, VPS35 levels are reduced. This reduction is associated with the formation of tau tangles inside neurons, as well as the accumulation of amyloid-beta outside neurons. Eventually, these deposits of abnormal proteins interrupt neuron activity and contribute to neurodegenerative disorders, including Alzheimer's disease.
In the new study, the researchers investigated the effects of a pharmacological chaperone on protein sorting in mice engineered to develop Alzheimer's disease as they age. Mice were treated from a young age, before they began to show signs of disease. As the animals grew older, they were tested for effects on memory and learning.
Dr. Praticò's team found that, compared to untreated mice destined for Alzheimer's disease, the treated animals had much better memory and behaved just like normal, or wild-type, mice. When the researchers examined neurons from treated mice, they observed significant decreases in tau tangles, as well as decreases in amyloid-beta plaques—another type of  aggregate that contributes to Alzheimer's disease. The researchers further noticed that VPS35 levels were restored and the junctions where neurons come together to exchange information, known as synapses, were fully functional following the pharmacological chaperone therapy.
"Relative to other therapies under development for Alzheimer's disease, pharmacological chaperones are inexpensive, and some of these drugs have already been approved for the treatment of other diseases," Dr. Praticò said. "Additionally, these drugs do not block an enzyme or a receptor but target a cellular mechanism, which means that there is much lower potential for side effects. All these factors add to the appeal of pursuing pharmacological chaperone drugs as novel Alzheimer's treatments."
Before moving to trials in human patients, however, Dr. Praticò plans to next investigate the effects of pharmacological chaperone therapy in older mice. "Because our most recent investigation was a preventative study, we want to know now whether this therapy could also work as a treatment for patients already diagnosed with Alzheimer's ," he added.
https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-019-0350-4
https://en.wikipedia.org/wiki/Pharmacological_chaperone
https://en.wikipedia.org/wiki/VPS35

Tuesday, March 24, 2020

FDA Approves Vyondys 53 (golodirsen) Injection for the Treatment of Duchenne Muscular Dystrophy (DMD) in Patients Amenable to Skipping Exon 53

In continuation of my update on oligonucleotide.

VYONDYS 53 (golodirsen) Structural Formula - Illustration



Sarepta Therapeutics, Inc. (NASDAQ:SRPT), the leader in precision genetic medicine for rare diseases, today announced that the U.S. Food and Drug Administration (FDA) has approved Vyondys 53™ (golodirsen). Vyondys 53 is an antisense oligonucleotide from Sarepta’s phosphorodiamidate morpholino oligomer (PMO) platform, indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients with a confirmed mutation amenable to exon 53 skipping. This indication is based on a statistically significant increase in dystrophin production in skeletal muscle observed in patients treated with Vyondys 53, which is reasonably likely to predict clinical benefit for those patients who are exon 53 amenable. Consistent with the accelerated approval pathway, the continued approval of Vyondys 53 may be contingent on confirmation of a clinical benefit in this post-marketing confirmatory trial.

Sarepta’s placebo-controlled, post-marketing confirmatory trial to support the Vyondys 53 accelerated approval – titled ESSENCE – is currently enrolling and expected to conclude by 2024.
Hypersensitivity reactions, including rash, pyrexia (fever), pruritis, urticaria (hives), dermatitis, and skin exfoliation have occurred in patients who were treated with Vyondys 53. Renal toxicity was observed in animal studies. Although not observed in the clinical studies with Vyondys 53, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. The most common adverse reactions that occurred in at least 20% of Vyondys 53-treated patients and more frequently than in placebo-treated patients were headache (41%), pyrexia (41%), fall (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%).
Following a New Drug Application (NDA) submission to and review by the Division of Neurology Products (the Review Division) for Vyondys 53, which the Review Division recommended for approval, the Office of Drug Evaluation 1 issued a complete response letter (CRL) in August of 2019. Thereafter, Sarepta made a formal dispute resolution request as outlined in relevant FDA Guidance. With the support of the Review Division, the matters raised in the CRL were rapidly evaluated and resolved by Dr. Peter Stein, Director of the Office of New Drugs (OND). OND granted the Company’s appeal and Sarepta re-submitted its NDA to the Review Division, which worked expeditiously to review and approve Vyondys 53.
“Today is monumental for Sarepta and, more importantly, for the DMD community,” said Doug Ingram, president and chief executive officer, Sarepta. “Vyondys 53, our second approved exon-skipping RNA therapy for DMD, may treat up to 8% of the DMD community, representing those patients who have a confirmed exon 53 amenable mutation. Along with EXONDYS 51® (eteplirsen), we now offer treatment options for approximately 20% of those with DMD in the U.S.”
Ingram continued, “In the span of four months, we commenced and completed the formal dispute resolution process culminating in the grant of our appeal, resubmitted our NDA and obtained an approval – a great benefit to DMD patients awaiting treatment. This unprecedented timing could not have been achieved without the commitment of the Review Division under the leadership of Dr. Billy Dunn, and the Office of New Drugs, which expeditiously heard and granted our appeal. Along with the DMD community, we owe our gratitude to both the Review Division and the OND for their objective, evidence-based approach to this review, for their fairness, and for the sense of urgency with which they addressed and resolved the CRL and granted this approval.”
“With the approval of Vyondys 53, up to another 8% of Duchenne families will have a therapy to treat this devastating disease,” said Pat Furlong, founding president and chief executive officer, Parent Project Muscular Dystrophy (PPMD). “For 25 years, PPMD has been working with researchers, clinicians, industry, and the Duchenne community to find treatments for all people living with Duchenne. And while we need to ensure that these approved therapies are accessible for patients, today we celebrate this approval and thank Sarepta for their continued leadership in the fight to end Duchenne.”
Vyondys 53 is priced at parity to EXONDYS 51, the price of which has not increased since its launch in 2016. Patients and physicians can access more information at www.SareptAssist.com or by calling 1-888-727-3782.

About Vyondys 53

Vyondys 53 is an antisense oligonucleotide indicated for the treatment of Duchenne muscular dystrophy in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. Vyondys 53 uses Sarepta’s proprietary phosphorodiamidate morpholino oligomer (PMO) chemistry and exon-skipping technology to bind to exon 53 of dystrophin pre-mRNA, resulting in exclusion, or “skipping,” of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 53 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein.
https://www.rxlist.com/vyondys-53-drug.htm


Friday, October 26, 2018

Food scientists turn soy milk residue into healthy probiotic drink

In continuation of my update on Soy Milk
Food scientists at the National University of Singapore (NUS) have given okara - the residue from the production of soy milk and tofu, and is usually discarded - a new lease of life by turning it into a refreshing drink that contains live probiotics, dietary fiber, free isoflavones and amino acids. By encapsulating these nutrients in a beverage, they can be easily absorbed into the body, and promote gut health.
Created using a patented, zero-waste process, the tasty drink can be stored at room temperature for up to six weeks and still retain high counts of live probiotics to better deliver health effects. This is unlike commercially available probiotic drinks which are mainly dairy-based and require refrigeration to maintain their levels of live probiotics. These beverages also have an average shelf-life of four weeks, and do not contain free isoflavones, which have a host of health benefits.
"Okara has an unpleasant smell and taste - it smells fishy, tastes bland, and has a gritty mouthfeel. Our breakthrough lies in our unique combination of enzymes, probiotics and yeast that work together to make okara less gritty, and give it a fruity aroma while keeping the probiotics alive. Our final product offers a nutritious, non-dairy alternative that is eco-friendly," said project supervisor Associate Professor Shao-Quan Liu, who is from the Food Science and Technology Program at the NUS Faculty of Science.
Turning unwanted soy pulp into a nutritious drink
About 10,000 tonnes of okara are produced yearly in Singapore. As it turns bad easily, causing it to give out an unpleasant smell and a sour taste, okara is usually discarded by soy food producers as food waste.
The idea of using fermentation to produce a drink from okara was first conceived by Ms Weng-Chan Vong, a PhD student from the NUS Food Science and Technology Program. She recounted, "Fermented soy products, such as soybean paste and miso, are common in Asian food culture. When I was young, my grandparents explained to me how these fermented foods are made. The fermentation process was like magic to me - it transforms bland food into something delicious."
"During my undergraduate studies at NUS, I worked on a project to examine how soy milk can be infused into different food items, and I realized that a huge amount of okara was being discarded. It occurred to me that fermentation can be one good way to convert unwanted okara into something that is nutritious and tastes good," she added.
Under the guidance of Assoc Prof Liu, Ms Vong took a year to devise a novel recipe that converts okara into a beverage that is fruity and refreshing. She experimented with 10 different yeasts and four different enzymes before coming up with an ideal combination.
The final recipe uses the probiotic strain Lactobacillus paracasei L26, the Viscozyme ® L enzyme and the Lindnera saturnus NCYC 22 yeast to convert the okara into a nutritious drink that achieves a minimum of 1 billion probiotics per serving, which is the current recommendation by the International Scientific Association for Probiotics and Prebiotics to achieve maximum health benefits. The drink, which takes about one and a half days to produce, also contains free isoflavones, which are naturally occurring antioxidants that maintain cardiovascular health, as well as dietary fiber and amino acids.
Next step: Refining the recipe for commercialization
The NUS researchers have filed a patent for their novel technique, and are currently experimenting with different enzymes and microorganisms to refine their recipe. They are also looking to collaborate with industry partners to introduce the drink to consumers.
"In recent years, the food and beverage industry has been intensifying efforts to develop products that appeal to consumers who are increasingly health conscious. Our new product offers soy food manufacturers a viable solution to reduce waste, and also enables them to provide a healthy and eco-friendly beverage for their customers," said Assoc Prof Liu.