Science Current Events | Science News |

New compound holds promise for treating Duchenne MD, other inherited diseases

June 28, 2012

RTC 13 effectively counteracts 'nonsense' mutation that causes disorder

Scientists at UCLA have identified a new compound that could treat certain types of genetic disorders in muscles. It is a big first step in what they hope will lead to human clinical trials for Duchenne muscular dystrophy.

Duchenne muscular dystrophy, or DMD, is a degenerative muscle disease that affects boys almost exclusively. It involves the progressive degeneration of voluntary and cardiac muscles, severely limiting the life span of sufferers.

In a new study, senior author Carmen Bertoni, an assistant professor in the UCLA Department of Neurology, first author Refik Kayali, a postgraduate fellow in Bertoni's lab, and their colleagues demonstrate the efficacy of a new compound known as RTC13, which suppresses so-called "nonsense" mutations in a mouse model of DMD.

The findings appear in the current online edition of the journal Human Molecular Genetics.

"We are excited about these new findings because they represent a major step toward the development of a drug that could potentially treat this devastating disease in humans," Bertoni said. "We knew that the compounds were effective in cells isolated from the mouse model for DMD, but we did not know how they would behave when administered in a living organism."

Nonsense mutations are generally caused by a single change in DNA that disrupts the normal cascade of events that changes a gene into messenger RNA, then into a protein. The result is a non-functioning protein. Approximately 13 percent of genetic defects known to cause diseases are due to such mutations. In the case of DMD, the "missing" protein is called dystrophin.

For the study, Bertoni and Kayali collaborated with the laboratory of Dr. Richard Gatti, a professor of pathology and laboratory medicine and of human genetics at UCLA. Working with the UCLA Molecular Shared Screening Resource facility at the campus's California NanoSystems Institute, the Gatti lab screened some 35,000 small molecules in the search for new compounds that could ignore nonsense mutations. Two were identified as promising candidates: RTC13 and RTC14.

The Bertoni lab tested RTC13 and RTC14 in a mouse model of DMD carrying a nonsense mutation in the dystrophin gene. While RTC14 was not found to be effective, RTC13 was able to restore significant amounts of dystrophin protein, making the compound a promising drug candidate for DMD. When RTC13 was administered to mice for five weeks, the investigators found that the compound partially restored full-length dystrophin, which resulted in a significant improvement in muscle strength. The loss of muscle strength is a hallmark of DMD.

The researchers also compared the level of dystrophin achieved to the levels seen with another experimental compound, PTC124, which has proved disappointing in clinical trials; RTC13 was found to be more effective in promoting dystrophin expression. Just as important, Bertoni noted, the study found that RTC13 was well tolerated in animals, which suggests it may also be safe to use in humans.

The next step in the research is to test whether an oral formulation of the compound would be effective in achieving therapeutically relevant amounts of dystrophin protein. If so, planning can then begin for clinical testing in patients and for expanding these studies to other diseases that may benefit from this new drug.

University of California - Los Angeles

Related Dystrophin Current Events and Dystrophin News Articles

Target gene identified for therapies to combat muscular dystrophy
Researchers at the University of SĂ£o Paulo's Bioscience Institute (IB-USP) in Brazil have shown that a gene called Jagged1, or JAG1 for short, could be a target for the development of new approaches to treat Duchenne muscular dystrophy (DMD), a genetic disorder characterized by progressive muscle degeneration.

Manipulating cell signaling for better muscle function in muscular dystrophy
Every heart beat and step in our daily lives is dependent on the integrity of muscles and the proteins that keep them strong and free of injury as they contract and relax.

Gene therapy treats all muscles in the body in muscular dystrophy dogs
Muscular dystrophy, which affects approximately 250,000 people in the U.S., occurs when damaged muscle tissue is replaced with fibrous, fatty or bony tissue and loses function.

New research sees zebrafish earn their stripes in the fight against muscular dystrophy
New research published today in the journal eLife has demonstrated a new method for observing the behaviour of the protein Dystrophin in a living animal cell, in real-time. This breakthrough may provide a key to understanding how to treat the genetic disease, Muscular Dystrophy.

Alternative strategy for gene replacement shows promise in duchenne muscular dystrophy
A gene therapy approach to treating the progressive muscle wasting disorder Duchenne muscular dystrophy (DMD) that does not replace the mutated DMD gene but instead delivers the gene for ITGA7, a protein in skeletal muscle, led to reduced symptoms and significantly extended life span in a mouse model of severe DMD.

Muscle fibers grown in the lab offer new model for studying muscular dystrophy
Skeletal muscle is one of the most abundant tissue types in the human body, but has proven difficult to produce in large quantities in the lab.

Cardiac stem cell therapy may heal heart damage caused by Duchenne muscular dystrophy
Researchers at the Cedars-Sinai Heart Institute have found that injections of cardiac stem cells might help reverse heart damage caused by Duchenne muscular dystrophy, potentially resulting in a longer life expectancy for patients with the chronic muscle-wasting disease.

Scientists pioneer microscopy technique that yields fresh data on muscular dystrophy
Scientists at USC have developed a new microscopy technology that allows them to view single molecules in living animals at higher-than-ever resolution.

Muscular dystrophy: Repair the muscles, not the genetic defect
A potential way to treat muscular dystrophy directly targets muscle repair instead of the underlying genetic defect that usually leads to the disease.

Discovery of new form of dystrophin protein could lead to therapy for some DMD patients
Scientists have discovered a new form of dystrophin, a protein critical to normal muscle function, and identified the genetic mechanism responsible for its production.
More Dystrophin Current Events and Dystrophin News Articles

Dystrophin: Gene, Protein and Cell Biology (French Edition)

Dystrophin: Gene, Protein and Cell Biology (French Edition)
by Susan C. Brown (Editor), Jack A. Lucy (Editor), Marlin Bobrow (Editor)

This book is concerned with advances in research on dystrophin, and how its absence gives rise to muscular dystrophy. It is the first book to address relationships between the molecular structure and function of dystrophin since the structure of the gene for this protein was elucidated in 1988. The volume covers recent advances in knowledge on the structure of both the dystrophin gene and its associated promoters, and on the protein itself. Functional interactions of dystrophin and its related proteins in the environment of the plasma membrane are a central feature of the book. Other aspects considered are the expression of the dystrophin complex in muscle, in the brain, and at the neuromuscular junction. The book concludes with discussions of muscle regeneration, gene therapy of Duchenne...

The dystrophin protein family: Localization and physiological role

The dystrophin protein family: Localization and physiological role
by Diana Hazai (Author)

Duchenne muscular dystrophy (DMD)is one of the most common, severe human disease. Mutations in the DMD gene are responsible for the disorder. Due to the mutations, dystrophin proteins are not expressed or expressed in functionally impaired form. The dystrophins are members of the dystrophin-associated protein complex (DAPC)located in the sarcolemma in the striated muscle. The DAPC links the extracellular matrix to the actin-based cytoskeleton and anchors signalling molecules. DAPC proteins are also localized in neurons and glia cells within the central nervous system and they interact with each other building up different types of DAPCs. Finding out the localization, colocalization of the DAPC proteins and the construction of the DAPC within the brain was the aim of the...

Structure and function of Native and edited dystrophin rods.

Structure and function of Native and edited dystrophin rods.
by Neha Sahni Ping Yu (Author)

Book by Sahni, Neha

Biochemical Characterization of Dystrophin Spectrin Type Repeats: Biochemical and Biophysical analysis of Dystrophin Spectrin Type Repeats with emphasis on structure  prediction.

Biochemical Characterization of Dystrophin Spectrin Type Repeats: Biochemical and Biophysical analysis of Dystrophin Spectrin Type Repeats with emphasis on structure prediction.
by Ismaeel Muhamed (Author)

The dystrophin gene and its association with dystrophies is a prime factor to study the spectrin type repeats (STR) of dystrophin. There are 24 triple helical rods of Dystrophin STRs having four flexible hinges. The exon skipping and tissue specifity of the dystrophin isoforms make its function diverse. The deletion of STRs and mutations causes instability of the protein leading to diseases. This work studies the stability of spectrin type repeat, which would identify the roles and probably understand the function of individual spectrin repeat in diseases. The repeats are subjected to urea and temperature and the helical stability is measured. Structure prediction methods were worked on d1617 dystrophin spectrin double repeat to predict its structure which resulted in 4...

The Right to Try: How the Federal Government Prevents Americans from Getting the Lifesaving Treatments They Need

The Right to Try: How the Federal Government Prevents Americans from Getting the Lifesaving Treatments They Need
by Darcy Olsen (Author)

The inspiring state-by-state campaign to allow sick Americans access to experimental treatments currently blocked by the government, chronicled by the woman leading the charge.Should you need the government’s permission to try to save your own life? Today, the FDA regulates medications available to Americans. But it takes an average of ten years to bring a new drug to market. Every day thousands of Americans die unnecessarily from fatal diseases for which lifesaving treatments that now exist or are being developed are ruled too “dangerous” for commercial distribution. But how does that FDA standard apply to someone in the terminal stages of cancer or ALS?Right to Try is filled with stories of heroism and heartbreak—of courageous Americans who beat illnesses no one thought could be...

Muscle 2-Volume Set: Fundamental Biology and Mechanisms of Disease

Muscle 2-Volume Set: Fundamental Biology and Mechanisms of Disease
by Academic Press

A valuable study of the science behind the medicine, Muscle: Fundamental Biology and Mechanisms of Disease brings together key leaders in muscle biology. These experts provide state-of-the-art insights into the three forms of muscle--cardiac, skeletal, and smooth--from molecular anatomy, basic physiology, disease mechanisms, and targets of therapy. Commonalities and contrasts among these three tissue types are highlighted. This book focuses primarily on the biology of the myocyte. Individuals active in muscle investigation--as well as those new to the field--will find this work useful, as will students of muscle biology. In the case of hte former, many wish to grasp issues at the margins of their own expertise (e.g. clinical matters at one end; molecular matters at the other), adn this...

Thompson & Thompson Genetics in Medicine, 8e

Thompson & Thompson Genetics in Medicine, 8e
by Robert L. Nussbaum MD FACP FACMG (Author), Roderick R. McInnes CM MD PhD FRS(C) FCAHS FCCMG (Author), Huntington F Willard PhD (Author)

Updated to reflect the newest changes in genetics, Thompson & Thompson's Genetics in Medicine returns as one of the most favored texts in this fascinating and rapidly evolving field. By integrating the classic principles of human genetics with modern molecular genetics, this medical reference book utilizes a variety of learning tools to help you understand a wide range of genetic disorders. Acquire the state-of-the-art knowledge you need on the latest advances in molecular diagnostics, the Human Genome Project, pharmacogenetics, and bio-informatics.Better understand the relationship between basic genetics and clinical medicine with a variety of clinical case studies. Recognize a wide range of genetic disorders with visual guidance from more than 240 dynamic illustrations and high-quality...

Junk DNA: A Journey Through the Dark Matter of the Genome

Junk DNA: A Journey Through the Dark Matter of the Genome
by Nessa Carey (Author)

For decades after the identification of the structure of DNA, scientists focused only on genes, the regions of the genome that contain codes for the production of proteins. Other regions that make up 98 percent of the human genome were dismissed as "junk," sequences that serve no purpose. But researchers have recently discovered variations and modulations in this junk DNA that are involved with a number of intractable diseases. Our increasing knowledge of junk DNA has led to innovative research and treatment approaches that may finally ameliorate some of these conditions.Junk DNA can play vital and unanticipated roles in the control of gene expression, from fine-tuning individual genes to switching off entire chromosomes. These functions have forced scientists to revisit the very meaning...

Neuromuscular Disorders: Management and Treatment

Neuromuscular Disorders: Management and Treatment
by Saunders

Neuromuscular Disorders presents a multi-disciplinary approach to the management and therapeutic treatment of the full range of neuromuscular disorders and resulting complications. Dr. Tulio Bertorini and a contributing team of the world’s leading authorities in the field provide the latest tools and strategies for minimizing disability and maximizing quality of life.Effectively treat your patients using the latest management tools and targeted therapeutic strategies. Manage all neuromuscular disorders as well as resulting complications through comprehensive coverage of diagnosis and evaluations, treatments, and outcomes. Apply the multi-disciplinary approach of an expert in clinical neuromuscular care and a team of world-renown contributors. Easily refer to tools for diagnosis,...

Muscle Biopsy: A Practical Approach

Muscle Biopsy: A Practical Approach
by Saunders

Muscle Biopsy: A Practical Approach gives you all of the unparalleled guidance necessary to effectively interpret and diagnose muscle biopsy specimens for the full range of diseases in both adults and children. Authored by Dr. Victor Dubowitz, an internationally renowned figure in the field of muscle disease, this medical reference book takes an integrated approach to diagnosis and assessment of muscle biopsies that includes clinical, genetic, biochemical, and pathological features. It's the comprehensive, up-to-date coverage you need to evaluate muscle disorders with confidence.Consult this title on your favorite e-reader, conduct rapid searches, and adjust font sizes for optimal readability.Bridge the gap between clinical syndromes/disorders and their underlying pathologies with the...

© 2015