Our preclinical supporting studies were approximately $1.5 million. RSRT Awards $337,336 to Michela Fagiolini at Boston Children’s Hospital. We know that having too much MECP2 from conception and through early development causes serious symptoms. In the letter to the FDA, the senators called it “unconscionable” that the falsified data would be submitted for the approval process, particularly since the gene therapy was initially researched with funding from the federal government. Gene therapy promised a lot early on, before the technology was very developed. – Brian Kaspar. Cobb:  The studies have also shown that the level of MeCP2 protein produced by the gene therapy is not producing any obvious defects in its own right and it therefore seems possible to deliver protein within limits that are tolerable to cells. To profoundly impact a disorder with as many varied and debilitating symptoms as Rett Syndrome, it is likely that intervention must be directed toward the very root of the problem. When Dr. Cobb visited our lab recently he provided critical expertise in a short visit that saved us an enormous amount of time and effort if we had been working alone. Gray:  Most of my work is done in collaboration with other labs, and I’m very comfortable doing research that way. Consortium members are also working on the following key issues: 1) Vector optimization – The vector is the Trojan horse that delivers the gene into a cell. AveXis only notified the FDA about the manipulation following the regulatory approval. Brian Kaspar (middle) at an RSRT workshop. I recently caught up with the investigators to discuss this novel collaboration: Brian Kaspar (Nationwide Children’s Hospital) From left moving clockwise:Sarah Sinnet (Gray lab), Steve Gray, Brian Kaspar, Stuart Cobb, Saurabh Garg (Mandel lab), Kamal Gadalla (Cobb lab).

Why Rett? Why now? The reversal of symptoms in mice was quite remarkable, but there are many challenges to translating that to a reversal in girls and women with Rett. This new group comes after the success of RSRT’s MECP2 Consortium, established in 2011, that led to the initial encouraging gene therapy findings. Taking over for the Kaspars will be Page Bouchard, a longtime veteran of the pharma industry. 4) Optimizing how much gene therapy to deliver – the scientists are delivering low, medium and high dosages in an attempt to see how much is needed to get a therapeutic effect without generating toxic side effects. This Consortium allows us to learn from each other’s studies. This will inevitably lead to more rapid progress in addressing the various challenges. With a budget of $1.5 million the members of this international gene therapy collaboration are charged with tackling the necessary experiments to get us to clinical trials as quickly as possible. Expectations should have been tempered somewhat while the science was worked out, but instead the field moved too fast and people got hurt. The first gene therapy product received full regulatory approval last year in Europe.

Create a free website or blog at WordPress.com.Ben Eastaugh and Chris Sternal-Johnson. For example, if you deliver intravenously (via the blood stream) there is concern that a large amount of vector will end up in the liver potentially causing toxicity. Brian Kaspar Program Director—Pre Release Treatment Program at Texas Department of Criminal Justice—Hamilton Unit Bryan/College Station, Texas Area 37 connections August 20, 2013 in Uncategorized | Tags: Adrian Bird, Brian Kaspar, Dan Lioy, Gail Mandel, Helene Cheval, MECP2, MECP2 Consortium, Nationwide Children's Hospital, OHSU, rett, rett syndrome, Rett Syndrome Research Trust, RSRT, Saurabh Garg, University of Edinburgh | Leave a comment. Coenraads: What are the strengths your lab brings to the table? As you know, there is a lot at stake. I have a small and fairly specialized lab. Another advantage is that it’s not neurodegenerative – neurons don’t die. Our trip to the US for both the Consortium meeting and visit to UNC was very productive. Join Facebook to connect with Brian Kaspar and others you may know. The previous studies that we performed in collaboration with the Kaspar group were promising in showing that expression of a good copy of MeCP2, delivered systemically with AAV9, ameliorated Rett-like symptoms in female mice and prolonged survival significantly in affected males. Today, AveXis revealed that Brian Kaspar and Allan Kaspar, the company’s head of research and development, are no longer with the company. In a brief announcement, AveXis said the Kaspar brothers have not been involved in any operations at AveXis since early May, seemingly ahead of the U.S. Food and Drug Administration’s approval of Zolgensma. Mandel:  As in any area of science, there are proponents and detractors. Create a free website or blog at WordPress.com. Frankly, it is a good time to be in the field. The Cobb lab shares Brian’s excitement about the consortium’s efforts and the potential for gene therapy to counteract the root cause of Rett Syndrome.

Mandel: I have been fortunate enough to be part of a productive collaboration funded by RSRT to work on how MeCP2 functions normally, and in mutants, and to do, with Kaspar’s group and Adrian Bird, the initial pilot proof of principle for gene therapy for Rett, using AAV9 vectors. Kaspar: We have successfully navigated two programs from bench research to human clinical trials. Gray: That said, the devil is in the details. [Spanish translation] Interestingly, the view within industry has been more accepting, perhaps due to the massive shift towards biologicals (alternatives to classical small molecule drugs) that has occurred in recent years. Parents all over the world will be waiting anxiously to hear about your progress. In addition to Gail Mandel, other members of the Consortium are Stuart Cobb (University of Glasgow), Steven Gray (University of North Carolina at Chapel Hill), and Brian Kaspar (Nationwide Children’s Hospital). As a laboratory, we have bolstered our Rett efforts and are making great progress in testing the safety and developing the pre-clinical data necessary for developing a treatment. This is a small example of the many benefits we have had from working together in a collaborative fashion. It’s a great group of scientists and I’m privileged to be a part of it. Such greed cannot be condoned by the FDA,” the senators said in the letter. Gail Mandel with lab membersDan Lioy and Saurabh Garg. Also, the MECP2 Duplication Syndrome suggests that too much MECP2 is bad. The path is starting to look much clearer to get there. Coenraads: Dr. Kaspar, tell us a bit about your experience bringing the Spinal Muscular Atrophy project to clinical trial. The move was not unexpected as Novartis entered crisis management to contain another scandal. Bernie Sanders and Elizabeth Warren. By Alex Keown. We developed the treatment about 3 ½ years after starting the project, which included testing the treatment in the laboratory and developing an approach that should translate to humans. FREE Background Report. Kaspar: We’ve learned that a single one-time administration of a gene therapeutic can have a clinically meaningful result in the workhorse rodent model of this disease, even when delivered later in life. The FDA-required safety studies were another $0.75 million. To get around this problem a vector that de-targets the liver would be very useful.

The Cobb lab shares Brian’s excitement about the consortium’s efforts and the potential for gene therapy to counteract the root cause of Rett Syndrome. We are encouraged with our delivery studies to target cells efficiently in the brain, where one requires the proper expression of MECP2. The advantages gained by labs working collaboratively are clear: speed (four labs contributing to the work that has to be done), real time sharing of information means more brainpower and broader perspectives for problem solving. We aren’t experts at everything, and it is much more efficient to collaborate with someone that has expertise than try to develop it on your own. Why now? Mandel:  I am a basic science lab and I have strengths in applying state of the art molecular tools to questions related to gene therapy. Brian Kaspar is on Facebook. The revelation of the data manipulation, plus the $2.1 million list price tag for Zolgensma, has raised the ire of multiple federal lawmakers, including Democratic presidential candidates Sens. Special thanks to our funding partners, the Rett Syndrome Research Trust UK and the Rett Syndrome Research & Treatment Foundation. Our goal is to get to clinical trials.

The senators, along with other colleagues from the upper chamber of Congress, issued letter to the FDA demanding that the regulatory agency take action against AveXis. The parent company has stood behind the data submitted to the FDA. We also were able to compare and standardize how we score neurological features seen in the mice. There is a great deal of excitement and hope in the field today. Similar “mini-gene” work is also underway in the lab of Adrian Bird and will be shared with the Consortium. We discovered the unique capacity for AAV9 to cross the blood brain barrier in 2009, in 2010 we were in progress to have the longest living SMA mouse in the world. With any transformative findings there will be disbelievers. “It is unconscionable that a drug company would provide manipulated data to federal regulators in order to rush its product to market, reap federal perks, and charge the highest amount in American history for its medication. For Rett we need a vector that can get into the brain and spread efficiently throughout the organ. We wish to express our gratitude to all of our generous supporters and the parent organizations that make this progress possible. I think transformative therapies go through this track of failing and then triumphing. We are now trying to improve the expression level of delivered MeCP2 by redesigning the vector, according to ideas and experimental results presented at the Consortium meetings. We are excited and hopeful to help children with SMA type 1. Join Facebook to connect with Brian Kaspar and others you may know. Press Release [Spanish Translation] [German Translation], Video interview with Dr. Mandel & lab members. The senators urged the FDA to hold AveXis accountable “through all appropriate criminal, civil and regulatory actions against the company” in order to “restore public confidence in the agency’s approval process.”. Two of the big outstanding questions then are: 1) Will this be true for humans and 2) Can we add MeCP2 back to patients and also achieve reversal? As well as coordinating efforts, the consortium also enables us to cross validate key experiments to ensure findings are robust and reproducible across laboratories. January 28, 2014 in Uncategorized | Tags: Adrian Bird, Brian Kaspar, Gail Mandel, gene therapy, MECP2, MECP2 Gene Therapy Consortium, Monica Coenraads, Nationwide Children's Hospital, OHSU, rett, rett syndrome, Rett Syndrome Research Trust, RSRT, Steve Gray, Stuart Cobb, University of Edinburgh, University of Glasgow | Leave a comment, [Italian translation] Mandel:  It has been known for some time now that when MeCP2 is expressed genetically in cells throughout an MeCP2-deficient mouse, major Rett symptoms are reversible in mice. But does the same hold true if extra MECP2 is delivered later in life? All rights reserved. In essence they need to design a “mini-MECP2 gene’.

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