Correcting nonsense mutations with CRISPR/cas9?

Correcting nonsense mutations with CRISPR / Cas9?

Would it be possible to correct nonsense mutations with CRISPR/Cas9? Some patients with DMD have a point mutation (nonsense) that leads either to the absence or to the abnormal function of dystrophin. The objective of Professor Jacques P. Tremblay’s team is to develop therapies for DMD due to such mutations.

In the last three years, new variations of the CRISPR/Cas9 technology, called base editing, permit to change a single nucleotide pair into another one. Professor Jacques P. Tremblay’s team will use this technology to correct the point mutation present in the MDX mouse model and 28 mutations detected in Canadian DMD patients according to the Canadian Neuromuscular Disease Registry database. Their knowledge and acquired experience will then subsequently be used to treat point mutations responsible for other hereditary neuromuscular diseases.

 

Professor Jacques P. Tremblay will be on Découverte on November 3 at 6:30 pm on Radio Canada. Découverte|Radio-Canada 

 

The human DNA

The human DNA present in each of our cells contains all the genetic information that we have inherited from our parents (e.g., eye colour, hair colour), including mutations responsible for hereditary diseases. 

This DNA is formed by only four chemical molecules called nucleotides:

  • A: adenosine
  • T: thymidine
  • C: cytosine
  • G: guanine

The DNA is a double helix formed by nucleotide pairs. Half of our genome originates from our mother and the other half from our father. We have received 3.2 billion nucleotide pairs from each parent. Genes coding for proteins that make our cells are sequences of these nucleotide pairs.

 

What is CRISPR/Cas9 technology?

CRISPR/cas9 technology is a technology that was first identified in bacteria. Bacteria were using this to cut up the genome of the viruses that were infecting them. About five years ago, researchers noticed that this technology allows not only to cut up virus genes but that it can also cut genes in animals, plants and especially in humans. Learn more here > Genetic engineering offers real hope of advancement.

 

About Professor Jacques P. Tremblay

Jacques P. Tremblay received a B.Sc. in Biochemistry from McGill University in 1970, and a Ph.D. in Neuroscience from UCSD (University of California in San Diego) in 1974. From 1975 to 1976, he was a postdoctoral fellow at the Laboratory of Neurobiology of l’Hôpital de L’Enfant-Jésus. His group is currently using CRISPR/Cas9 technology to correct the dystrophin gene, creating an additional deletion to produce a hybrid exon of the dystrophy gene, which not only restores the expression of dystrophin but also produces dystrophin with a regular structure.

To learn more about the work of Professor Jacques P. Tremblay: Centre de recherche du CHU de Québec

 

Interview with Jacques Tremblay

We wish to connect you, the DMD community, with the professors. We hope this video will be a good medium for understanding how CRISPR/Cas9 technology work, as related to DMD.

DAKOTA’S BIG SMILE

Notes from the “Living with DMD” web-doc Tecima Productions team.

Our small production team travelled across Canada, meeting with families whose children have Duchenne muscular dystrophy (DMD). We met with Dakota (age 6), Anakin (age 11) and Carl (age 35) at critical moments in their journey. Our goal was to produce a web-doc in three acts, to raise awareness about DMD by living it through the eyes of the families suffering because of it. This degenerative muscle disease, for which there is no cure, usually leads to premature death in the patient’s early twenties. When we met the Albert family, we discovered a happy family, despite the suffering. But mom Kristen’s smiles and laughter—that resonate throughout the household hide a great sadness: knowing that the family’s middle son Dakota is afflicted with DMD.

A Painful Projection of the Future

Today, this ebullient early-thirties couple are the proud parents of (get this) a family of 5 children. When the diagnosis fell, Dakota was just three years old. Projecting such a tragic fate for a 3-year old (at the time) is beyond a broken heart. It’s also a scenario that follows you in all of your life’s activities.

 

— Kristen Albert—Excerpt from the documentary Living with DMD. “You know, you have this outlook on your family, thinking, you’ll have happy, healthy kids, and then, all of a sudden, we find out that our middle boy is going to die before he should. It’s hard to deal with that every day.”

 

A DMD Diagnosis… and autism

Unfortunately, in addition to DMD, Dakota has also been diagnosed with autism. This reality has brought the family to face another dilemma: whether or not to administer corticosteroids that can increase the symptoms of autism.

 

—Aaron Albert—Excerpt from the documentary Living with DMD. “I would like to stay away from steroids for as long as possible. Because my son has autism as well, he’s already having some developmental issues, behaviour-wise. He has to deal with anger and shows aggressive behaviour; steroids can make that worse. They can cause obesity, osteoporosis and behaviour issues. We’ve decided that we can’t really make that worse right now; he needs help with his autism first.”

 

Despite all this sadness and the dilemmas he faces, Dakota has one of the most beautiful smiles we’ve ever seen. Mom Kristen’s laughter lights up their home because, despite the suffering, they are happy people.

How can you help us? Watch our documentary, continue reading our article, and share them with your communities. Every action counts.

 

Enjoy watching and thank you for sharing in your community.

 

The documentary “Living with DMD” is produced by www.tecima.com

 

* It should be noted that the Albert family’s story is a specific case, each DMD and autism diagnosis has its own unique characteristics and details. Taking corticosteroids or not in this situation is the personal decision of each parent. The Albert family has also had access to a corticosteroid-like treatment since the documentary was shot.

More about corticosteroïdes here.

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Positive data with vamorolone in DMD

Santhera Announces Presentation by ReveraGen of Positive 18-Month Data with Vamorolone in Duchenne Muscular Dystrophy

 

La Force is happy to share this press release provided by Santhera Pharmaceuticals, October 7, 2019, > PRESS RELEASE <

 

Santhera Pharmaceuticals announces the presentation of data showing continued improvement of muscle function and improved tolerability compared with corticosteroids of 18-month vamorolone treatment in Duchenne muscular dystrophy (DMD). These top-line data were presented on October 5 by Eric Hoffman, Ph.D., CEO of ReveraGen at the World Muscle Society (WMS) congress.

In a late-breaking presentation at the WMS international conference in Copenhagen, Denmark, ReveraGen presented motor function and tolerability data from 23 DMD patients treated with 2.0 or 6.0 mg/kg/day with vamorolone for at least 18 months in the ongoing VBP15-LTE study.

 

Eric Hoffman, Ph.D., Chief Executive Officer of ReveraGen – “These data demonstrate that vamorolone treatment results in persistently improved motor function in DMD patients, similar to that of corticosteroids. Importantly, however, vamorolone treatment over a period of 18 months showed better tolerability with less corticosteroid-specific side effects, including no stunting of the growth of DMD children.”

 

Vamorolone is a first-in-class steroidal anti-inflammatory investigational drug in development as a treatment for DMD to substitute standard corticosteroids (prednisone, deflazacort). This trial is an extension study of the VBP15-003 trial in which 48 DMD patients treated for 6 months over a broad dose range (0.25 to 6.0 mg/kg/day) showed dose-related improvements in multiple gross motor outcomes. Upon exiting this 6-month trial, patients and their physicians preferred to continue vamorolone treatment. 45 boys transitioned to the 2-year long-term extension study VBP15-LTE and all doses were increased to 2.0 or 6.0 mg/kg/day of vamorolone.

At the WMS conference, Dr. Hoffman presented data from 23 patients treated with 2.0 or 6.0 mg/kg/day vamorolone for at least 18 months. Vamorolone treatment consistently and significantly improved standardized motor function outcomes measured as velocity to stand from supine, to run/walk 10 meters and to climb 4 stairs from baseline to month 18. Motor function outcomes for vamorolone treated patients also were consistently better than outcomes for age-matched, steroid naïve patients from an external natural history study (velocity to stand from supine: p=0.085; run/walk 10 meters: p=0.005; climb 4 stairs: p=0.036; all in favour of vamorolone treatment).

Vamorolone compared to standard corticosteroids

Motor function outcomes of vamorolone-treated DMD boys were compared to age-matched prednisone-treated patients from an external control group. Both vamorolone and prednisone treated groups showed similar improvements in these gross motor outcomes, demonstrating that vamorolone exerts therapeutic efficacy similar to standard corticosteroids. Importantly, vamorolone-treated boys showed normal growth rates, and less physician-reported weight gain and Cushingoid features compared to published studies of prednisone and deflazacort. These findings confirm earlier data that indicate a better tolerability profile of vamorolone compared to standard corticosteroids.

Together with previously reported molecular and clinical data, the new 18-month data suggest that dissociative steroidal drug vamorolone maintains efficacy and decreases adverse effects typically reported for corticosteroids in the treatment of DMD. Vamorolone has been granted Orphan Drug status in the US and Europe and has received Fast Track and Rare Pediatric Disease designations by the US FDA.

About Vamorolone – first-in-class dissociative steroid

Vamorolone is a first-in-class drug candidate that binds to the same receptors as corticosteroids but modifies the downstream activity of the receptors. This has the potential to ‘dissociate’ efficacy from typical steroid safety concerns and therefore could replace existing corticosteroids, the current standard of care in children and adolescent patients with DMD. There is a significant unmet medical need in this patient group as high dose corticosteroids have severe systemic side effects that detract from treatment compliance and patient quality of life.

The currently ongoing 48-week Phase IIb VISION-DMD study is designed as a pivotal trial to demonstrate efficacy and safety of vamorolone compared with prednisone and placebo in 120 boys aged 4 to <7 with DMD that have not yet been treated with corticosteroids. Vamorolone is being developed by US-based ReveraGen BioPharma Inc. with participation in funding and design of studies by several international non-profit foundations, the US National Institutes of Health, the US Department of Defense and the European Commission’s Horizon 2020 program. In November 2018, Santhera acquired from Idorsia the option to an exclusive sub-license to vamorolone in all indications and all countries worldwide (except Japan and South Korea).

Clinical trial in Canada

About Santhera

Santhera Pharmaceuticals is a Swiss specialty pharmaceutical company focused on the development and commercialization of innovative medicines for rare neuromuscular and pulmonary diseases with a high unmet medical need. Santhera is building a Duchenne muscular dystrophy (DMD) product portfolio to treat patients irrespective of causative mutations, disease stage or age. A marketing authorization application for Puldysa® (idebenone) is currently under review by the European Medicines Agency. Santhera has an option to license vamorolone, a first-in-class dissociative steroid currently investigated in a pivotal study in patients with DMD to replace standard corticosteroids. Santhera out-licensed ex-North American rights to its first approved product, For further information, please visit www.santhera.com. Raxone® and Puldysa® are trademarks of Santhera Pharmaceuticals

About ReveraGen BioPharma

ReveraGen was founded in 2008 to develop first-in-class dissociative steroidal drugs for Duchenne muscular dystrophy and other chronic inflammatory disorders. The development of ReveraGen’s lead compound, vamorolone, has been supported through partnerships with foundations worldwide, including Muscular Dystrophy Association USA, Parent Project Muscular Dystrophy, Foundation to Eradicate Duchenne, Save Our Sons, JoiningJack, Action Duchenne, CureDuchenne, Ryan’s Quest, Alex’s Wish, DuchenneUK, Pietro’s Fight, Michael’s Cause, and Duchenne Research Fund. ReveraGen has also received generous support from the US Department of Defense CDMRP, National Institutes of Health (NCATS, NINDS, NIAMS), and European Commission (Horizons 2020).

Links

Translarna™ (ataluren) Slows Disease Progression in Patients with DMD

PTC Therapeutics announces new real-world analysis demonstrating Translarna™ (ataluren) slows disease progression in patients with Duchenne muscular dystrophy

 

La Force is happy to share this press release provided by PTC Therapeutics, Inc.  Oct 4, 2019  > PRESS RELEASE <

Lung function data from the STRIDE Registry show a trend toward delay of the decline of pulmonary function compared with those in CINRG Duchenne Natural History

PTC Therapeutics, Inc. announced that data from STRIDE, the first international registry for patients with Duchenne muscular dystrophy due to a nonsense mutation receiving Translarna™ (ataluren), demonstrate that Translarna preserves lung function in children and adolescents compared with a matched cohort in a long-term natural history study. The real-world analysis was presented at the International Annual Congress of the World Muscle Society.

 

Stuart Peltz, Ph.D., Chief Executive Officer, PTC Therapeutics – “Across ambulation, physical function and lung function, the STRIDE data demonstrate that patients receiving Translarna preserved function for years longer than patients receiving standard of care. These are real-world results that provide clinicians and regulators with the true picture of patient response to treatment.”

 

Researchers evaluated FVC, a traditional measure of lung function in Duchenne patients that correlates with disease progression and mortality. The STRIDE data showed that 32.1% of the standard of care patients from the natural history cohort had an FVC of <50%, compared to only 2.2% of patients receiving Translarna after a mean total exposure of 633 days. The data also indicates that Translarna significantly preserved patients’ ability to stand up from lying and climbing stairs compared with natural history.

After the loss of ambulation and loss of the use of the arms, the respiratory muscles of people with Duchenne start to progressively deteriorate, leading to the risk of life-threatening respiratory complications and the need for ventilation support. Patients with a predicted FVC of <50% are considered to be in the late non-ambulatory stage of Duchenne. To conduct the analysis, patients from the STRIDE Registry were matched against a comparable cohort of patients from the Cooperative International Neuromuscular Research Group Natural History Study, based on their propensity for disease progression.

These latest data build on the STRIDE registry –  time-to-event analysis, which demonstrated that the median age at which patients on Translarna lost the ability to stand up from lying in under 5 seconds (the first key clinically significant Duchenne milestone) is 12 years – 3 years later than seen with natural disease progression in untreated children [9.1 years].

 

Dr. Eugenio Mercuri, Professor, Pediatric Neurology, Catholic University, and author of the study –  “Respiratory failure is the primary cause of disability and death in patients with Duchenne and monitoring and preserving lung function is a key clinical priority. As the muscles progressively weaken, breathing and effective coughing gets more difficult and patients. It’s very encouraging to see positive lung function results in a real-world setting and provides reassurance that ataluren is slowing disease progression, eventually become dependent on ventilation support, which is distressing for families.”

 

The demographic characteristics of the study population from the STRIDE Registry were published in August this year in the Journal for Comparative Effectiveness Research.

About Translarna (ataluren)

Ataluren, discovered and developed by PTC Therapeutics, Inc., 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. Translarna, tradename ataluren, is licensed in the European Economic Area for the treatment of nonsense mutation Duchenne muscular dystrophy in ambulatory patients aged two years and older. Ataluren is an investigational new drug in the United States.

More about Translarna, watch the video.

 

About the STRIDE Registry

An observational study building a patient data repository that provides real-world experience regarding the use of treatments in clinical practice.

What does STRIDE mean?

STRIDE stands for ‘Strategic Targeting of Registries and International Database of Excellence.’ The STRIDE registry has been set up in neuromuscular disorders (NMD) within a STRIDE-NMD umbrella registry concept that will enable a broader disease area registry to be created. Learn more on TREAT-NMD

STRIDE is a collaborative partnership between TREAT-NMD and PTC Therapeutics, led by a Steering Committee comprised of leading experts in Duchenne, patient advocates from around the world and PTC representatives.

 

About TREAT-NMD

TREAT-NMD is a network for the neuromuscular field that provides an infrastructure to ensure that the most promising new therapies reach patients as quickly as possible. Since its launch, in January 2007 the network’s focus has been on the development of tools that industry, clinicians and scientists need to bring novel therapeutic approaches through preclinical development and into the clinic, and on establishing best-practice care for neuromuscular patients worldwide. The network has developed from its European roots to become a global organization that brings together leading specialists, patient groups and industry representatives to ensure preparedness for the trials and therapies of the future while promoting best practice today.

 

About Duchenne Muscular Dystrophy

Primarily affecting males, Duchenne muscular dystrophy is a rare and fatal genetic disorder that results in progressive muscle weakness from early childhood and leads to premature death in the mid-twenties due to heart and respiratory failure. It is a progressive muscle disorder caused by the lack of functional dystrophin protein. Dystrophin is critical to the structural stability of all muscles, including skeletal, diaphragm, and heart muscles. Patients with Duchenne can lose the ability to walk as early as age ten, followed by loss of the use of their arms. Duchenne patients subsequently experience life-threatening lung complications, requiring the need for ventilation support, and heart complications in their late teens and twenties.

 

About PTC Therapeutics, Inc.

PTC is a science-led, global biopharmaceutical company focused on the discovery, development and commercialization of clinically-differentiated medicines that provide benefits to patients with rare disorders. PTC’s ability to globally commercialize products is the foundation that drives investment in a robust pipeline of transformative medicines and our mission to provide access to best-in-class treatments for patients who have an unmet medical need.

Pioneers in DMD therapy

 

Translarna™ (ataluren) in Canada

Translarna™ (ataluren) has not received marketing authorization in Canada. This treatment must, first and foremost, be evaluated and approved for the Canadian market by Health Canada. To approve a drug, Health Canada must ensure that it meets certain safety, efficiency and quality requirements.

La Force DMD hopes that Translarna™ (ataluren) will be marketed in Canada as soon as possible so that all young patients can benefit.

 

 

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PolarisDMD Trial in DMD has exceeded target enrollment

Phase 3, PolarisDMD trial of edasalonexent in DMD has exceeded target enrollment

 

La Force is happy to share the latest edition of the Catabasis Connection newsletter

 

Catabasis Pharmaceuticals, Inc. announced today the completion of enrollment for the Phase 3 PolarisDMD trial of edasalonexent in Duchenne muscular dystrophy (DMD). The target enrollment of 125 boys was exceeded due to strong interest from their 40 clinical sites in 8 countries and the support of patient advocacy organizations. Top-line results from the Phase 3 PolarisDMD trial are expected in the fourth quarter of 2020 and the trial is anticipated to support a New Drug Application (NDA) filing in 2021.

PRESS RELEASE

 

Joanne Donovan, M.D., Ph.D., Chief Medical Officer of Catabasis “We are thrilled to reach this important milestone. The interest and feedback from families and trial sites has been overwhelmingly positive. At a time when there are multiple trials for Duchenne, we are very pleased that physicians and families chose the Phase 3 PolarisDMD trial for edasalonexent. Edasalonexent has the potential to be a foundational therapy, providing benefit to boys, regardless of their underlying mutation, with the potential to benefit muscle function, as well as cardiac function and bone health. We look forward to completing the trial next year and are working diligently toward the goal of making edasalonexent available to patients.”

 

The PolarisDMD trial enrolled 130 boys ages 4 to 7 with any mutation type and who had not been on steroids for the past 6 months. The trial is a randomized, double-blind, placebo-controlled trial with 2 to 1 randomization such that two boys receive edasalonexent for each boy that receives a placebo. At the completion of 52 weeks, all boys and their eligible siblings are expected to have the option to enroll in GalaxyDMD, an open-label extension study designed to assess the long-term safety of edasalonexent. Boys can begin or continue treatment with an approved exon skipping therapy in the GalaxyDMD trial, which has a streamlined schedule with visits to trial sites every six months. Read more about these studies here.

 

About Edasalonexent (CAT-1004)

Edasalonexent (CAT-1004) is an investigational oral small molecule designed to inhibit NF-kB that is being developed as a potential foundational therapy for all patients affected by DMD, regardless of their underlying mutation. In DMD the loss of dystrophin leads to chronic activation of NF-kB, which is a key driver of skeletal and cardiac muscle disease progression. Our ongoing global Phase 3 PolarisDMD trial is evaluating the efficacy and safety of edasalonexent for registration purposes. Edasalonexent is also being dosed in the open-label extension trial GalaxyDMD. In our MoveDMD Phase 2 trial and open-label extension, we observed that edasalonexent preserved muscle function and substantially slowed disease progression compared to rates of change in a control period, and significantly improved biomarkers of muscle health and inflammation. The FDA has granted orphan drug, fast track, and rare pediatric disease designations and the European Commission has granted orphan medicinal product designation to edasalonexent for the treatment of DMD. For a summary of clinical results, please visit www.catabasis.com.

 

About Phase 3 PolarisDMD Trial

The global Phase 3 PolarisDMD trial is a one-year, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of edasalonexent in patients with DMD. The trial enrolled patients ages 4 to 7 regardless of mutation type who had not been on steroids for at least 6 months. Boys on a stable dose of eteplirsen were also eligible to enroll. The primary efficacy endpoint is change in the North Star Ambulatory Assessment score after 12 months of treatment with edasalonexent compared to placebo. Key secondary endpoints include the age-appropriate timed function tests: time to stand, 4-stair climb and 10-meter walk/run. Assessments of growth, cardiac and bone health are also included as important potential areas of differentiation. For each boy that receives a placebo, two boys are receiving 100 mg/kg/day of edasalonexent and after 12 months, all boys are expected to receive edasalonexent in the open-label extension study GalaxyDMD. The PolarisDMD trial design was informed by discussions with regulators as well as input from treating physicians, patient organizations and families of boys affected by Duchenne. Top-line results from the Phase 3 PolarisDMD trial are expected in the fourth quarter of 2020. More information about the Phase 3 PolarisDMD clinical trial is available on clinicaltrials.gov.

 

About Catabasis

The mission of Catabasis Pharmaceuticals is to bring hope and life-changing therapies to patients and their families. There lead program is edasalonexent, an NF-kB inhibitor in Phase 3 development for the treatment of Duchenne muscular dystrophy. For more information on edasalonexent and the Phase 3 trial, please visit www.catabasis.com.

 

About La Force DMD

The Force’s mission is to unite the DMD community to raise awareness around a common objective: that of providing access to new treatments as fast as possible and to participate in the funding of promising research projects. Where access to treatments for rare diseases is concerned, it is essential that our community be strong: each member must be an active spokesperson who helps raise awareness for DMD among the general public, as well as for the challenges associated with access to treatment.

 

Edasalonexent is an investigational drug that is not yet approved in any territory.