# Steering the Clinical Translation of Delivery Systems for Drugs and Health Products
## 2 Lectures
### Session C: Relevance and State of the Art of Clinical Studies in Drug Release and Targeting
#### 2.3.2 Clinical Testing in Children: The Case of Givinostat in Duchenne Muscular Dystrophy  
[PERSON]  
Italfarmaco Group, 20126 Milan, Italy; [EMAIL_ADDRESS]  
Italfarmaco is developing Givinostat for the treatment of Duchenne Muscular Dystrophy (DMD), a rare degenerative, X-linked recessive genetic disorder with estimated incidence of 1 in 5000 live births, caused by mutations in the dystrophin gene. Figure 4: EVs from stem /progenitor cells as a paracrine/endocrine mechanism. In DMD, mutations in the dystrophin gene disrupt the open-reading frame, resulting in an absence of functional dystrophin, a critically important part of the protein complex that connects the cytoskeletal actin of a muscle fiber to the extracellular matrix. Lack of dystrophin causes repetitive muscle damage. In a normal muscle, the physiological repair process removes the damaged muscle fibers and reconstitutes normal muscle fibers. In DMD, on the other hand, the repair process leads to a combination of new muscle fibers, fatty replacement and fibrosis, with the two latter components progressively prevailing as a process called fibroadipose degeneration. This detrimental outcome typically compromises muscle function, alters the tissue environment, and probably limits the potential effectiveness of regenerative approaches. As described by [PERSON] et al., fibrosis is already significant at one year of age in DMD patients constituting approximately 16% of a muscle biopsy (3% in age matched controls) and remains relatively constant until 7 years of age. At this age, there is an important increase in the proportion of fibrosis that reaches approximately 30% of muscle biopsy between 7 and 10 years of age. Similarly, MRI studies have shown that fat infiltration is already present at 5 years of age and constantly increases. DMD is characterized by progressive symmetrical muscular weakness that affects proximal muscles more than distal muscles, often accompanied by calf muscle pseudo hypertrophy. Significant motor deficits may be present during the first year of life, but diagnosis is usually made between the ages of 3 to 5 years when the affected patients begin to show waddling gait, toe walking, and difficulty climbing stairs. Over time, ambulation becomes increasingly abnormal, and by 8 years of age, most patients lose the ability to rise from the floor and climb stairs, and often fall while walking. By 12 to 14 years of age, most lose the ability to walk and the heart and respiratory muscles also are affected. Upper limb, cardiac, and diaphragmatic muscles progressively weaken during adolescence. After 18 years all patients are affected by cardiomyopathy. Only a few survive beyond the third decade; most patients die because of respiratory complications and heart failure due to cardiomyopathy. There are still no curative treatments for such a debilitating disease and the current management of the disease is based on prevention and management of complications. Corticosteroids (e.g., prednisone or deflazacort) have been demonstrated to slow the rate of muscle weakness when initiated in ambulatory boys, however, the use of corticosteroids is limited by all the potential side effects, including weight gain, cataracts, osteopenia, and avascular necrosis. Recently, the European Medicines Agency has granted a conditional approval to Ataluren, which targets nonsense mutations as the cause of DMD, which is relevant for only 13% of DMD population, or approximately 2000 patients in the United States (US) and 2500 patients in the European Union (EU). In addition, the FDA has granted an accelerated approval to Eteplirsen, which targets DMD gene mutations skippable with exon 51 skipping, which are relevant for only 13% of DMD population, or approximately 2000 patients in the United States (US) and 2500 patients in the European Union (EU). In light of the above considerations, it becomes evident that an unmet therapeutic need exists for the treatment of this disabling and fatal condition.