1860-1900

Duchenne de Boulogne, after whom Duchenne muscular dystrophy is named. (From “The Founders of Neurology,” courtesy Charles C. Thomas Publisher.)

• French physician Guillaume Duchenne de Boulogne and British physician Edward Meryon describe what would later be called Duchenne muscular dystrophy (DMD)

• Microscope used to study muscle in health and disease

1930-1960

• Different types of muscular dystrophies recognized

• X-chromosome-linked inheritance pattern for DMD confirmed

• German physician Peter Emil Becker describes a muscle disease similar to DMD and with same inheritance pattern but less severe and allowing longer survival (1950s); it later will be called Becker muscular dystrophy (BMD)

1960-1975

• Location of basic DMD defect (nervous system, muscles or blood flow) debated

• Elevated serum creatine kinase (CK) levels begin to be used to detect DMD carriers

• First studies report on the benefit of prednisone in DMD

1975-1980

• MDA conference on site of DMD defect establishes muscle-fiber membrane defect hypothesis as front-runner to explain DMD

• Research attention shifts to muscle-fiber membrane

1980-1984

• Emerging techniques in molecular genetics localize gene underlying DMD to a specific region of the X chromosome and show BMD is likely due to a defect in the same gene

Louis M. Kunkel, whose team identified the dystrophin gene in 1986.

Kevin Campbell

1984-1988

• Using different approaches, Louis M. Kunkel at Harvard Medical School in Boston and Ronald Worton at the Hospital for Sick Children in Toronto narrow the region of the X chromosome containing the gene that, when defective, causes DMD

• Gene responsible for DMD is identified by Louis M. Kunkel’s team

• Protein made from DMD gene is described, named dystrophin and localized to muscle-fiber membrane

1989-1994

• Kevin Campbell at the University of Iowa shows that dystrophin protein is not directly inserted into the muscle-fiber membrane, but is attached via a cluster of proteins that would become known as the dystrophin-glycoprotein complex (DGC)

• DGC is further described, and proteins in it are found to be significantly deficient in DMD and reduced to a lesser degree in BMD

• Severity of DMD or BMD determined to be correlated with amount of dystrophin present at muscle-fiber membrane (the more dystrophin, the less severe the symptoms)

• Location and type of flaw in dystrophin gene determined to be correlated with DMD or BMD severity in some cases

• Cell transplantation technique called myoblast transfer helps DMD-affected mice

• Myoblast transfer explored in several human trials but survival of transplanted cells and dystrophin production from them are minimal

• Corticosteroid prednisone confirmed to slow the progression of DMD in several clinical trials

• Transferring functional dystrophin genes into DMD-affected tissues (gene therapy) explored in cells and mice

1995-2000

• Dystrophin gene miniaturized to facilitate gene therapy

• Methods of delivering dystrophin gene, with or without viral transporters, explored

• Dystrophin gene further miniaturized to fit inside adeno-associated viral shell, which becomes preferred delivery method

• Stem cells to treat DMD come under consideration

• Mice with DMD found to benefit from high levels of utrophin (a protein similar to dystrophin), whether bred to produce extra utrophin or given utrophin genes via gene therapy

2001-2005

• Corticosteroid prednisone found effective in slowing progression of DMD in more trials

• American Academy of Neurology publishes guidelines for prednisone use in DMD

• MD-CARE Act passed in U.S. Congress in 2001 with MDA’s help; mandates establishment of centers of excellence in muscular dystrophy

• MDA and National Institutes of Health co-fund MD centers of excellence at University of Washington-Seattle, University of Rochester (N.Y.) and University of Pittsburgh

• Dystrophin-deficient mice given a compound to block myostatin protein show increased muscle mass and strength

Scientists at PTC Therapeutics have received MDA support to develop PTC124.

• L-arginine and molsidomine found to increase levels of utrophin (possible substitute for dystrophin) in mice

• Constructs called antisense oligonucleotides found to block flawed parts of genes and allow nearly normal protein molecules to be produced in mice; technique dubbed “exon skipping”

• Compound called PTC124 found to allow cells to ignore molecular stop signs and produce normal dystrophin protein molecules

• MDA gives PTC Therapeutics $1.5 million to develop PTC124 for DMD

• Trial of PTC124 opens to boys with DMD with “premature stop codon” mutations

2006-2009

• Follistatin protein found to turn off myostatin and increase muscle mass in mice

• Plans begin for multinational trial to optimize corticosteroid use in DMD

Andrew Kilbarger, 8, receiving an injection of dystrophin genes in March 2006.

• PTC124 found to restore dystrophin in about half of boys with DMD in 28-day trial

• PTC Therapeutics launches larger, longer trial of PTC124

• Exon-skipping trial in Netherlands finds compound developed with MDA support allows dystrophin production in all four DMD-affected boys tested

• Exon-skipping trial opens in United Kingdom using a second compound developed with MDA support

• Some 300 exon skipping compounds developed to target different parts of dystrophin gene

• First U.S. clinical trial of gene therapy in DMD begins

• Dystrophin gene injections into an arm muscle judged safe and well tolerated in six boys with DMD; plans are made to test three additional boys at higher dose

• Intravenous injection of highly miniaturized dystrophin genes restores muscle structure and function in mice

• Method of delivering genes without viral transporters developed

• Molecule identified that allows utrophin to be produced all around muscle fibers instead of in one small place

Giulio Cossu

• Dystrophin-deficient mice produce dystrophin after an arterial injection of muscle-derived stem cells

• Dystrophin-deficient dogs produce dystrophin after receiving arterial injections of stem cells called mesoangioblasts that were taken from muscle tissue

• Pericyte-derived stem cells are identified in human muscle tissue by Giulio Cossu of the Istituto Scientifico San Raffaele, Milan, Italy

• Stem cells carrying an exon-skipping compound cause significant recovery of muscle form and function in dystrophin-deficient mice

• MDA-associated physicians join pulmonologists in releasing recommendations for use of anesthesia in DMD

• Transfer of utrophin gene via blood vessels found as effective as dystrophin gene transfer in mice with severe DMD-like disease

• Chemical switch called zinc-finger protein 51 found to activate utrophin production in DMD mice

• Raising level of sarcospan protein improves muscle health in DMD mice, probably by stabilizing utrophin

• MDA commits $1 million to new, 10-center Clinical Research Network, designating five centers as DMD-specific