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  1. #801
    Senior Member JohnLanders's Avatar
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    Third Patient Dies in Audentes' Gene Therapy Study for Neuromuscular Disease

    https://www.biospace.com/article/thi...cular-disease/


    A third pediatric patient involved in a gene therapy trial for a rare, neuromuscular disease conducted by Audentes Therapeutics has died. The trial remains on clinical hold and continues to indefinitely delay the company?s plans to seek regulatory approval for the treatment.

    This morning, Audentes, which was acquired by Astellas Pharma late last year, announced the death of the third patient involved in the company?s ASPIRO clinical trial evaluating AT132 in patients with X-linked Myotubular Myopathy (XLMTM). The disease is a life-threatening neuromuscular disease that almost exclusively impacts males and is characterized by extreme muscle weakness, respiratory failure and early death. XLMTM is caused by mutations in the MTM1 gene that lead to a lack or dysfunction of myotubularin, a protein that is needed for normal development. The disease affects approximately 1 in 40,000 to 50,000 newborn males. X-linked Myotubular Myopathy also disrupts normal bone development and can lead to fragile bones and joint deformities. Those diagnosed with the disease usually only survive into early childhood. Audentes? gene therapy uses an AAV8 vector to deliver a working copy of the myotubularin 1 gene into the patient to correct the disease.

    According to the company, preliminary findings indicate that the immediate cause of death in this patient was gastrointestinal bleeding. In its announcement this morning, Audentes said the patient was one of three study patients previously disclosed to have received AT132 at the dose of 3x1014 vg/kg who began to demonstrate signs of liver dysfunction within three to four weeks after dosing. All three patients demonstrated evidence of pre-existing hepatobiliary disease and Audentes noted that more than half of the patient enrolled in the ASPIRO study show evidence of pre-existing hepatobiliary disease. However, the company said that has not been associated with similar progressive liver dysfunction in any of the patients who received AT132 at the 1x1014 vg/kg dose nor in the other patients who received the 3x1014 vg/kg dose.

    The U.S. Food and Drug Administration placed the ASPIRO study on clinical hold in June after Audentes disclosed two pediatric patients who received the higher doses of the gene therapy developed sepsis and died.

    Audentes said it is closely monitoring all patients in the study. To date, 23 patients in the ASPIRO study have received AT132. Six patients received the gene therapy at the 1x1014 vg/kg dose and 17 patients received AT132 at the 3x1014 vg/kg dose, the company said. There are no other patients in the study known to be currently experiencing similar liver dysfunction, Audentes said.

    ?Audentes, together with the ASPIRO investigators and independent Data Monitoring Committee, continue to closely monitor all patients enrolled in the study. Additionally, Audentes? investigation regarding why these three patients developed progressive liver dysfunction is ongoing,? the company said in its announcement.

    The company plans to provide further information on the ASPIRO program based on both ongoing data collection and future regulatory status updates. Last year Audentes presented positive data from ASPIRO at the 24th International Annual Congress of the World Muscle Society. It was this data the company hoped to build upon in order to file a Biologics License Application with the FDA.

    https://medcitynews.com/2020/08/aste...therapy-trial/

    A third patient in the trial of a gene therapy for treating a rare and life-threatening neuromuscular disease that has already been placed on clinical hold has died, the company developing the therapy said Friday.

    Audentes Therapeutics ? which Japanese drugmaker Astellas acquired in December 2019 for $3 billion ? disclosed that the immediate cause of the death of a third patient in its Phase I/II ASPIRO trial of AT132 in X-linked myotubular myopathy, or XLMTM, was gastrointestinal bleeding.

    Shares of Astellas fell slightly on the over-the-counter market, where they trade in the U.S. The Tokyo-based company?s shares principally trade on the Tokyo Stock Exchange.

    The patient was one of three in the trial who had received the gene therapy at a dose of 300 trillion viral vectors per kilogram of body weight and had begun to demonstrate signs of liver dysfunction within three to four weeks after receiving the dose. The trial is enrolling boys up to the age of 5.

    All three of the patients demonstrated signs of pre-existing hepatobiliary disease, a term referring to disease of the liver and bile ducts or gall bladder. However, more than half of the patients enrolled into the study so far showed signs of such disease, though the gene therapy has not been associated with similar complications when administered at the 100 trillion vector per kilogram dose. To date, 23 patients have received AT132, including six at 100 trillion vectors and 17 at 300 trillion vectors.

    Audentes had previously said in late June that a patient in ASPIRO had died of sepsis, a month after another patient had also died.

    The announcement marks the second significant setback this week for gene therapies. On Wednesday, San Rafael, California-based BioMarin said the Food and Drug Administration had delivered a complete response letter for its application to secure approval for valoctocogene roxaparvovec, a gene therapy for hemophilia A. The news came as a surprise to many, given that the therapy was widely expected to win approval, and the company itself said the issues raised in the CRL had not been raised previously.

  2. #802
    Senior Member JohnLanders's Avatar
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    https://www.biopharmadive.com/news/a...deaths/580670/

    Update: On Aug. 20, Audentes announced that a third patient in the AT132 clinical trial has died.

    Dive Brief:
    Three children with a rare neuromuscular disease have died after receiving a high dose of a gene therapy in a clinical trial run by Audentes Therapeutics. The first two deaths were disclosed in letters sent by the company to patient groups in June. Audentes reported the third in August.
    Each of the children suffered liver problems that ultimately led to fatal complications. The most recent death occurred this month, though the letters revealed Audentes halted dosing of new patients before anyone had died. The Food and Drug Administration subsequently placed the study on a formal clinical hold.
    The gene therapy, called AT132, is designed to treat X-linked myotubular myopathy, a deadly disease caused by mutations in a single gene. Audentes, which was bought by Japan's Astellas Pharma for $3 billion in December, aimed to submit the treatment for approval this year, but those plans are now on hold, according to the letter.

    Dive Insight:
    Gene therapy has emerged rapidly in recent years because the field overcame safety concerns — most notably, the tragic death of teenager Jesse Gelsinger in a clinical trial in 1999 — that cooled initial optimism and slowed research.

    Newer methods to deliver genetic medicine have been proven out in clinical testing and two therapies are now approved in the U.S., both for rare inherited diseases. Others, for diseases like hemophilia and Duchenne muscular dystrophy, could soon follow.

    So far, this current wave of therapies have generally appeared safe. Encouraged, developers have tested higher and higher doses of gene therapies, aiming to expand their potential effectiveness. Higher doses are particularly important for neuromuscular diseases, since the treatment must travel through the bloodstream to reach the right tissue.

    Two years ago, gene therapy pioneer Jim Wilson — who led the Gelsinger trial at the University of Pennsylvania two decades ago — expressed concern about the strategy, fearing that pushing doses too high might lead to safety problems. Wilson and UPenn colleagues published a paper in the journal Human Gene Therapy noting liver and nerve damage in animal experiments with a certain type of gene therapy, and called for researchers to do more monitoring.

    While other gene therapy studies have been stopped in recent years, the deaths observed in Audentes' trial are particularly worrisome.

    Audentes' therapy has shown promise in early tests, enough for Astellas to pay $3 billion for the company in December. The pivotal study of AT132 began in 2017 and Audentes aimed to submit an application with the Food and Drug Administration this year.

    According to a letter Audentes sent to patient groups, however, that will no longer happen.

    On May 6, Audentes told the groups that a patient treated with a high dose of AT132 had died from sepsis. Two others also given the high dose had then experienced serious side effects.

    Six weeks later, on June 23, Audentes CEO Natalie Holles and chief medical officer Edward Conner sent a second letter explaining that one of those two had also died. That patient experienced progressive liver dysfunction, which didn't respond to standard treatment. His condition worsened and he ultimately died from a bacterial infection and sepsis.

    "There have been some incredible outcome measures with some of the children but the science needs to continue to evolve," said Alison Rockett Frase, president of the Joshua Frase Foundation, one of the patient groups Audentes wrote. "Our community is devastated by the loss of these two children," she added in an interview.

    On Aug. 20, Audentes reported that a third patient, also treated with a high dose of the gene therapy, had died from gastrointestinal bleeding.

    Audentes is still collecting information, monitoring all of the study's other patients and is in touch with regulators. A total of 17 patients have been treated with the high dose of AT132 — 300 trillion vector genomes per kilogram of body weight.

    "We are taking all necessary steps to understand these events and incorporate what we learn into our development plan going forward," Holles and Conner wrote in their letter. "We are currently assessing the impact on potential regulatory filing timelines, however we will not be filing in mid-2020 as previously communicated."

    They added, however, that none of these issues have been seen in the six patients treated with a lower dose, and all of those patients are "years out from treatment." Four of those patients had a history of liver or biliary system problems.

    All three of the patients who died also had evidence of pre-existing liver problems and showed signs of liver dysfunction within a month of treatment with AT132, Audentes said. All three patients with liver problems were of older age and heavier weight.

    None of those treated with a high dose currently have the type of liver dysfunction seen in the patients who died, Audentes said.

    Audentes uses a type of adeno-associated virus, called AAV8, to deliver its gene therapy. Other companies, including Ultragenyx, RegenxBio and Biogen are developing gene therapies that also rely on AAV8.

    The high dose Audentes uses is among the largest being tested in gene therapy.

    Ned Pagliarulo contributed reporting.

  3. #803
    Senior Member JohnLanders's Avatar
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    https://www.businessinsider.com/elon...is-mind-2021-2

    I swear this article sounds too much like conspiracy theories. The People surrounding Elon Musk need to verify this one.

    Elon Musk's human-computer-interface company, Neuralink, seems to be off to a strong start.

    "We've already got a monkey with a wireless implant in their skull, and the tiny wires, who can play video games using his mind," Musk said in an interview on the "Good Time Show" on the app Clubhouse on Sunday night.

    "One of the things we're trying to figure out is can we have the monkeys play mind 'Pong' with each other," he said. "That would be pretty cool."

    Neuralink has been testing neural interfaces on animals for years. In a video released last year, Neuralink demonstrated its work on a pig named Gertrude.


    In that video, Neuralink demonstrated its ability to record and try to predict actions based on a wired chip implanted in Gertrude's brain.

    But Musk said the video-game-playing monkey got a wireless chip that enabled it to control an electronic interface with its mind only.

    "He's not uncomfortable, and he doesn't look weird," Musk said. "And you can't even see where the neural implant went in."

    The wireless bit is particularly important, as it could eliminate the potential for infection that comes with wires protruding from organic material.

    "If you can do experiments with something that doesn't involve wires coming through the skin, that's going to improve the welfare of animals," Andrew Jackson, a neuroscience professor at the University of Newcastle, told Insider last year.

  4. #804
    Senior Member JohnLanders's Avatar
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    https://nypost.com/2021/02/03/elon-m...ter-this-year/

    . Elon Musk says that his neurotechnology company Neuralink could be launching human trials ?later this year.?

    Musk shared the news in response to a Twitter user who said he?d be willing to participate in the human trials, which would implant an artificial intelligence chip in humans? brains in hopes they could control technology just by thinking.



    I was in a car accident 20 years ago and have been paralyzed from the shoulders ever since. I?m always available for clinical studies at @Neuralink,? Twitter user Hamoon Kamai wrote to Musk on Sunday.

    ?Neuralink is working super hard to ensure implant safety & is in close communication with the FDA. If things go well, we might be able to do initial human trials later this year,? the Tesla CEO replied on Monday.

    Neuralink?s goal is also to help paralyzed patients easily interact with their cellphones or computers by implanting the brain chip, Musk previously said.

    The company began testing its chip on animals over the summer and used a pig for its experiment.



    Musk recently went on the audio-streaming app Clubhouse, where he said Neuralink has implanted the brain chip in a monkey and that it can play video games with its mind.

    ?We?ve already got a monkey with a wireless implant in their skull, and the tiny wires, who can play video games using his mind,? the billionaire tech entrepreneur said.

    ?One of the things we?re trying to figure out is, can we have the monkeys play mind-Pong with each other?? Musk added. ?That would be pretty cool.?

  5. #805
    Moderator raisedbywolves's Avatar
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    JL, this isn't a conspiracy theory, no matter how bad you want to make it one.

  6. #806
    Senior Member JohnLanders's Avatar
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    Quote Originally Posted by raisedbywolves View Post
    JL, this isn't a conspiracy theory, no matter how bad you want to make it one.
    I agree with you I just wish Elon Musk can show the data from his engineering and clinical staff of the neural implant in question that's been dubbed "Microchips in the Brain". I heard this for years but that was when conspiracy theorists were ranting about it though. It feels to be like boy cry wolf situation until the FDA says otherwise in this case.

    I want make sure this is correct here.

  7. #807
    Senior Member JohnLanders's Avatar
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    https://www.fiercebiotech.com/medtec...-patient-death

    Medtronic has launched a global recall of its Valiant Navion thoracic stent graft system, used to reinforce large blood vessels at risk of rupturing from an aneurysm or other injuries.

    The medtech giant notified physicians to cease using the implant until further notice, following reports of three stent fractures and the death of one patient in an international clinical trial of the device.

    The Valiant system is designed to fortify a weakened aorta from the inside and relieve the pressure on the vessel’s walls. The device is threaded through the body’s arteries via a minimally invasive catheter procedure to avoid open surgery and deploys a synthetic fabric tube supported by a metal stent scaffold.


    The Valiant Navion system. (Medtronic)
    According to Medtronic, two of the three stent fractures resulted in confirmed tears in the fabric tube, leaking blood out of the implant’s channel.

    In addition, patient imaging scans found that the stents in seven of the study’s 87 participants had widened to a diameter beyond the implant’s design specifications. The company said those cases need further evaluation to determine potential clinical effects, and it is currently conducting technical root cause investigations and reviewing follow-up trial imaging and commercial complaints.

    “There is nothing more important than the safety and well-being of patients,” Nina Goodheart, president of Medtronic’s structural heart and aortic business, said in a statement. “We treat matters of product safety with the highest priority and urgency. Our decision to implement this voluntary recall is necessary to ensure the utmost patient safety. As our investigation continues, we are committed to timely communication with physicians and regulatory bodies.”

  8. #808
    Senior Member JohnLanders's Avatar
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    https://sciencebasedmedicine.org/pha...ic-resistance/

    magine if we had a self-replicating programmable smart bomb that could target specific pathogenic bacteria and kill them, while being entirely safe for the host. It turns out, such a thing exists – they are viruses that evolved to kill bacteria, and they are called bacteriophages. Bacteriophages were first discovered in 1896, and they were an early rival to antibiotics for the treatment of bacterial infections. In the former Soviet Union, Poland, and other Eastern countries there was extensive research into so-called “phage therapy” but in the West antibiotics won out and phage therapy never caught on.

    But now phage therapy is gaining a second look, because a century later we have produced a dangerous level of antibiotic resistance. To some extent we may be coming to the end of the antibiotic era, as more and more multi-resistant strains of pathogenic bacteria emerge. This is a serious health problem that requires a multi-pronged solution. First, we need to minimize the emergence of resistance through best practices – not overusing antibiotics, using narrow rather than broad-spectrum antibiotics when able, and optimally completing antibiotic courses.

    In addition we need to develop new classes of antibiotics that work through novel mechanisms. There may come a time when we need to retire classes of antibiotics, to allow for resistance to wane while we depend on other classes. Perhaps we can come to a sustainable long-term cycle.

    Another possible solution is to take an entirely different approach to treating bacterial infections, and that’s where phage therapy comes in. The history of phage therapy is interesting, and there are a few lessons in there. Part of the reason phage therapy did not gain acceptance in the West is because the research was flawed. One early proponent, d’Herelle, did not use control groups in his clinical trials. He gave all the subjects phage therapy. This is a critical point for SBM – we often point out that, if the remarkable claims being made for a dubious treatment were in fact true, the proponents would be doing a disservice to humanity by not doing proper research to adequately prove it. The history of phage therapy, to some extent, bears out this concern.

    But also it seems that the technology we perhaps not quite ready for phage therapy. There were problems with purification, and contaminants could cause side effects at bad as the infection itself. Like antibiotics, some phages are lytic (they kill the bacteria) and some are not. Some early research unknowing did not use lytic phages. It was also difficult to maintain stable lines of therapeutic phages.

    The time, however, may be ripe for phage therapy. The technology to develop, quality control, and mass-produce biologics has evolved considerably, and the old problems that plagued phage therapy are entirely solvable. I liken this to the competition between electric and internal combustion engines. The gasoline engine won out a century ago, partly because of quirky contingency, but also partly because battery technology was very primitive. But now, with Li-Ion batteries, the time for electric vehicles is here. The same may be true for phage therapy.

    In fact, with advances in genetic engineering, using a therapy that is potentially genetically programmable may allow for the rapid development of specific phages for specific infections. This is similar to the emergence of mRNA vaccines – once we develop the mRNA vaccine platform, new vaccines can be designed in a matter of days, because we are getting really good at engineering and making mRNA.

    Where does the research stand? Some of the basic research is having to be repeated and updated, including preclinical and animal research. There are also some good clinical studies which support the safety and efficacy of phage therapy for specific infections. For example, a review of phage therapy for joint and bone infections concluded:

    Together, the reports identified by this review suggest that appropriately purified phages represent a safe and highly efficacious treatment option for complex and intractable bone and joint infections.

    Another review of phage therapy for superficial infections concluded:

    This review strongly suggests that the use of purified phage to treat superficial bacterial infections can be highly effective and, by various routes of administration, is safe and without adverse effects.

    A recent study also shows that using phage therapy in combination with antibiotics can be highly effective. The key is this:

    We characterized two bacteriophages, ΦFG02 and ΦCO01, against clinical isolates of Acinetobacter baumannii and established that the bacterial capsule is the receptor for these phages.

    The phages bind to the bacterial capsule in order to gain entry and kill the bacteria. Some of the bacteria did evolve resistance to the phage, however. They did so with loss-of-function mutations to genes responsible for the capsule. The bacteria without a capsule had no receptor site for the phage, so they were resistant. However, the capsule is what provides resistance to beta-lactam antibiotics, so those same bacteria were now susceptible to those antibiotics. The obvious conclusion here is that a combination of antibiotics and phage therapy can be very potent, because it would be extremely difficult for any bacterium to evolve resistance to both. This is the advantage of having different treatments that use wildly different mechanisms.

    Conclusion: The end of antibiotics and the rebirth of phages?
    At the same time that the antibiotic era is running into serious problems because of antibiotic resistance, we may be at the dawn of the era of phage therapy for bacterial infections. But phage therapy is actually over a century old, so what we are seeing is the rebirth of phage therapy with far more advanced technology for biologics in general, and genetic manipulation specifically. Further, the combination of antibiotic and phage therapy may be particularly potent.

    But the history of phage therapy also tells us that we cannot get so caught up in the hype that we skip over careful and rigorous clinical research.

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