October 2018 - La Force DMD

Tarantula venom for dmd

Here’s the latest news from the University of Buffalo (UB) about an experimental therapy called GsMTx4. Based on a molecule found in tarantula venom, this “protein” can prevent muscle mass loss and muscle damage in an animal model of Duchenne Muscular Dystrophy (DMD). Enjoy your reading and thank you for sharing these articles in the DMD community.

This research from UB, published last July in the magazine “Neuromuscular Disorders,” shows that this new drug significantly reduces the loss of muscle mass.

What Is GsMTx4?

GsMTx4 is a small protein, a peptide*, present in the venom of the tarantula. This protein works by preventing some ion channel activity in muscles without affecting the communication between nerve cells and muscle cells.

Frederick Sachs: “GsMTx4 represents an out-of-the-box treatment to slow the progression of DMD.”

Thomas Suchyna noted in a previous study that in addition to protecting muscles, GsMTx4 protected against cardiomyopathy, a common cause of death in patients with DMD.

Frederick Sachs: “Remarkably, we did not observe any side effects in mice in this study. The drug also has a long life so that subcutaneous injection may be needed only once a week.

The researchers concluded that GsMTx4 could also be complementary to other therapies, such as the anti-inflammatory agents and gene replacement strategies prescribed or studied in DMD.

GsMTx4 has already been licensed to Tonus Therapeutics and Akashi Therapeutics as a sublicence for further development.

Status:

By the spring of 2019, a new investigatory new drug application will be filed with the United States Food and Drug Administration (FDA). If successful, by 2020, Phase I/II studies in humans will be followed.

Manufactured by chemical synthesis, GsMTx4 is considered an ‘orphan drug,’ a designation that the FDA grants to promising therapies for rare diseases.

About DMD

Duchenne muscular dystrophy (DMD) is a disease that affects boys almost exclusively and whose incidence is 1 in 3,500. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. Duchenne muscular dystrophy (DMD)—for which no treatment is currently available—directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

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October 23, 2018/4 Comments/by Marie-Catherine Du Berger

News, Treatments

Patient registry demonstrating Translarna™ slows DMD progression

Here’s the latest news from PTC Therapeutics about Translarna™ (ataluren). In a recent press release, PTC announces that Translarna™ (ataluren) slows disease progression in children with Duchenne muscular dystrophy (DMD) caused by a nonsense mutation. Enjoy reading and thank you for sharing these articles within the DMD community.

Analysis of data to date shows Translarna Preserved Ambulation for up to 5 Years Compared to Natural History

The data show that children and adolescents receiving Translarna in the real-world setting are continuing to walk years longer than untreated children and are staying more physically able. A time-to-event analysis for loss of ambulation has shown that patients on Translarna had a median age of loss of ambulation of 16.5 years of age – up to 5 years later than seen with natural disease progression in untreated children. The data were presented as a late breaker at the 23rd International Annual Congress of the World Muscle Society in Argentina.

Stuart W. Peltz, Ph.D., CEO, PTC Therapeutics: “The results from the Registry data are critical because they further substantiate the results observed in our analyses of data from previous clinical trials studying Translarna in Duchenne. Delaying the loss of ambulation is critical to these patients, as it predicts the time to loss of pulmonary function and mortality.”

Dr. Eugenio Mercuri, Professor, Pediatric Neurology, Catholic University: “These initial data are very encouraging because they provide the first, real-world evidence for the impact of Translarna when used routinely, longer term. We are seeing children who have been exhibiting first clinical symptoms of Duchenne at approximately three years of age and yet are still able to walk years after they would normally be wheelchair-bound, which is what matters most to patients and their families.”

Filippo Buccella, an author of the study and Duchenne patient advocate: “Keeping a child with Duchenne walking for as long as possible is crucial not only to maintain independence, but to delay the rapid deterioration that usually follows loss of ambulation, including loss of the use of arms, which are essential for self-care, and respiratory and cardiac complications. As a father to a son with Duchenne, slowing the progression of this devastating disease is vital to maintaining the quality of life for the patient as well as the family.”

About Translarna ™ (ataluren)

Discovered and developed by PTC Therapeutics, Inc., Translarna ™ (ataluren) is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation. A nonsense mutation is an alteration in the genetic code that prematurely halts the synthesis of an essential protein. The resulting disorder is determined by which protein cannot be expressed in its entirety and is no longer functional, such as dystrophin in Duchenne muscular dystrophy. Read more here.

Ataluren in Canada

At this moment, PTC Therapeutics has not applied for marketing approval with Health Canada, but it has started a conversation with the legislator.

What is a nonsense mutation?

DMD is a devastating disease that is caused by mutations in the dystrophin gene. The mutations vary in nature and account for the deletion, faulty replication, or duplication of parts of the genetic blueprint or code for protein manufacture. In other words, mutations in the dystrophin gene disrupt how protein factories in cells read its genetic code while making the dystrophin protein. The result is the absence of functional dystrophin protein in skeletal and cardiac muscles.

A change in a single base (point) of DNA can prematurely end the translation of a gene into a protein. About 10 % to 15 % of single-point mutations are nonsense mutations. They occur during the reading of messenger RNA (mRNA), which copies the genetic code during the manufacturing process, into protein.

About DMD

Duchenne muscular dystrophy (DMD) is a disease that exclusively affects boys and whose incidence is 1 in 3,500. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

Positive results in the gene therapy micro-dystrophin trial to treat DMD

One of the objectives of our team is to inform you about new treatments. Here’s the latest news from Sarepta Therapeutics. They announce that at the 23rd International Congress of the World Muscle Society, Jerry Mendell, M.D., presented positive updated results from the four children dosed in the gene therapy micro-dystrophin trial to treat patients with Duchenne Muscular dystrophy. Enjoy reading and thank you for sharing these articles within the DMD community. -Press release from Sarepta Therapeutics: Sarepta news release.

A quick overview of gene therapy micro-dystrophin

This therapy uses a virus (the adeno-associated virus, or AAV) to deliver the micro-dystrophin, a shorter version of the dystrophin gene, which contains the minimum amount of information needed to produce a functional protein of dystrophin.* We are hopeful that, one day, micro-dystrophin will be a viable treatment for Duchenne muscular dystrophy (DMD).

What are the positive results?

Robust expression of micro-dystrophin
A significant decrease in creatine kinase (CK)
Improvements in all measured functions,
No serious adverse events (SAEs) were observed in the study.
Press release from Sarepta Therapeutics: Sarepta news release.

Words from Dr. Mendell

“The goal of this study was to validate what we observed in preclinical models. We observed efficient transduction of our vector, AAVrh74, to all muscle types; robust expression in skeletal muscles via the MHCK7 promoter; a reduction in creatine kinase levels; and a favorable safety profile. Similar to preclinical models, we also observed in this early study that robust expression has the potential to positively impact the natural course of disease progression.”

Words from Doug Ingram, Sarepta’s president and chief executive officer

“The encouraging results that we previously saw and reinforced in the fourth patient strengthen our resolve to rapidly move to a confirming trial and, assuming successful, to bring this therapy to the Duchenne community around the world with a sense of urgency.”

Words from Mr. Ingram

“These results create for us an obligation to patients around the globe living with and being damaged by this cruel disease. We are investing our energy, resources and creativity to moving the development forward, planning meetings with the FDA and other agencies around the world to take their input, building compelling access and reimbursement package, and establishing sufficient manufacturing capacity to fully serve the community if our program is successful.”

About DMD

Duchenne muscular dystrophy (DMD) is a disease that almost exclusively affects boys and whose incidence is 1 in 3,500. It is extremely rare that Duchenne muscular dystrophy (DMD) will affect girls. Those affected are usually diagnosed around the age of five, but symptoms may be visible from early childhood. It is a degenerative disease of the muscles caused by a genetic mutation. The Duchenne muscular dystrophy (DMD) – for which no treatment is currently available – directly affects skeletal muscles. Without treatment, the consequences of the disease are dire for those afflicted and their families.

About Sarepta Therapeutics

Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of precision genetic medicine to treat rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying Duchenne muscular dystrophy (DMD) drug candidates. For more information, please visit www.sarepta.com.

“Chimeric cells” for DMD?

Cells Restoring dystrophin in DMD

We’ve set a goal for ourselves of informing you about new treatments for Duchenne muscular dystrophy (DMD). Here are some very promising results: new research conducted by Dr. Maria Siemionow, professor of orthopedic surgery in the UIC College of Medicine. Good reading and thank you for sharing these articles within the DMD community.

What is the role of dystrophin in Duchenne muscular dystrophy (DMD)?

Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by a genetic mutation. Duchenne muscular dystrophy (DMD)—for which no treatment is currently available—directly affects the muscles. The simplest way to explain this disease is that a genetic mutation (i.e. a genetic defect) affects the gene responsible for the production of dystrophin. This genetic defect prevents the gene from producing dystrophin. In the absence of dystrophin, the muscles degenerate and become atrophied.

What are “chimeric cells”?

These cells, called “chimeric cells,” are made by combining a normal donor cell containing a functional copy of the dystrophin gene with a cell from a recipient with the disease. These cells were able to significantly improve muscle function when implanted into the muscles of a mouse model of the disease.

Research with promising results

Dr. Maria Siemionow, professor of orthopedic surgery in the UIC College of Medicine, and her team used “chimeric cells” in a study of model mice with DMD. The results are excellent: the boosted dystrophin levels by 37 percent and improved muscle function when implanted into the muscles of a mouse model of Duchenne muscular dystrophy. These cells remained viable and produced dystrophin for 30 days.

“Our results point to the long-term survival of these cells and helps establish the use of chimeric cells as a novel promising potential therapy for patients with Duchenne muscular dystrophy,” Siemionow said.

Clinical trials for on humans forthcoming

Dr. Maria Siemionow also mentioned that her team is looking forward to clinical trials in humans shortly. She went on to say:

“We are restoring dystrophin in such a way that the recipient won’t need to take anti-rejection therapy because the implanted chimeric cells can evade the recipient’s immune system. In traditional stem cell therapy, the implanted cells are 100 percent ‘other’ and anti-rejection medicine is needed in order to prevent the host immune system from destroying those foreign cells.”

How do chimeric cells work on humans?

If these cells were to be used to treat a patient with Duchenne muscular dystrophy, then normal muscle cells from the father or a close relative of the recipient would be fused with muscle cells from the patient. In contrast, chimeric cells can trick the recipient’s immune system into ignoring them. In lab tests, it was possible to bring the chimeric cells to express dystrophin.

Maria and Kris Siemionow, who are mother and son, have recently launched a company to develop their chimeric cells into a therapy to treat Duchenne muscular dystrophy called Dystrogen Therapeutics. The development of such a therapy is captivating, and its evolution deserves to be followed.

External links and special thanks to:

Dystrogen.com: Clinical stage regenerative medicine company

Scicasts.com: Human “Chimeric” Cells Restore Crucial Protein in Duchenne Muscular Dystrophy

Springer Link: Dystrophin Expressing Chimeric (DEC) Human Cells Provide a Potential Therapy for Duchenne Muscular Dystrophy

UIC College of Medicine

October 4, 2018/2 Comments/by Marie-Catherine Du Berger

Research

Jérôme Frenette: OPG for DMD

Professor Jérôme Frenette, himself lost two of his children due to a genetic disease. It’s, therefore, a decision from the heart that leads him to conduct today his research program on inherited diseases, like Duchenne Muscular Dystrophy (DMD). Professor Frenette understands very well the suffering of the people afflicted with the disease and their families. This understanding provides him with an additional motivation to conduct his work. This is an excellent conclusion to our web video series “Portrait of DMD.” We hope it will help you understand the functions and benefits of osteoprotegerin for DMD.

Jérôme Frenette: «I’ve lost two children to a genetic disease and I know very well what parents are currently experiencing with Duchenne muscular dystrophy, the suffering, the stress caused and the hope that is linked to these diseases. »

About Jérôme Frenette

Professor Jérôme Frenette is a researcher with a background in physical therapy and post-graduate training in muscle physiology and immunology at the University of California in Los-Angeles. The focus of his research program is to understand the link between osteoporosis and muscle atrophy/disease through one common pathway, i.e. the RANK/RANKL/OPG pathway. His team is developing new drugs that would potentially alleviate, in tandem, osteoporosis and muscle degeneration in Duchenne muscular dystrophy patients or other forms of bone and muscle diseases.

Can you explain your osteoprotegerin (OPG) research project?

Jérôme Frenette: We are working on the role of a protein, a protein that protects the bone, and we are interested in this protein. The big question is: could this bone protein also preserve muscle tissue? We know that the phenomenon of atrophy, of muscular dysfunction, happens at the same time as osteoporosis, so we tried to group these two diseases, bone, muscle, with a single protein which is osteoprotegerin, which, as its name says, protects the bone, and our work demonstrates that it also protects muscle tissue.

What would be the benefits of this treatment for DMD?

Jérôme Frenette: The benefit that these children could have in the very short term is to gain strength. Our work shows that there are very significant strength gains. The degeneration process, which begins at birth and continues until 20-25 years, could be delayed for several years. So, with a bone protein, we could succeed in protecting the muscle and the bone with our treatment.

When are the clinical trials for patients?

Jérôme Frenette: We’re relatively lucky because the molecule is relatively well characterized. Work has been done with a well-known company, Amgen, who have developed this protein. They even brought it to clinical trials in postmenopausal women. So, I think we can go much faster because there have already been clinical trials on this protein. A window of approximately 2 to 5 years may be considered for clinical treatment in children.

More information about Professor Jérôme Frenette: Centre de recherche du CHU de Québec

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Archive for month: October, 2018

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