Efficacy of stem cell therapy in ambulatory and nonambulatory children with Duchenne muscular dystrophy – Phase I–II

Abstract

PurposeDuchenne muscular dystrophy (DMD) is an X-linked recessive pediatric disorder that ultimately leads to progressive muscle degeneration. It has been known that cell-based therapies were used to promote muscle regeneration. The main purpose of this study was to investigate the effects of allogeneic Wharton jelly-derived mesenchymal stem cells therapy in Duchenne muscular dystrophy.Patients and methodsFour ambulatory and five nonambulatory male patients were assessed as having acceptance criteria. Gene expression and immunohistochemical analysis were performed for dystrophin gene expression. The fluorescent in situ hybridization method was used for detection of chimerism and donor–recipient compatibility. Complement dependent lymphocytotoxic crossmatch test and detection of panel reactive antigen were performed. All patients were treated with 2 × 106 cells/kg dose of allogeneic Wharton jelly-derived mesenchymal stem cells via intra-arterial and intramuscular administration. Stability was maintained in patient follow-up tests, which are respiratory capacity tests, cardiac measurements, and muscle strength tests.ResultsThe vastus intermedius muscle was observed in one patient with MRI. Chimerism was detected by fluorescent in situ hybridization and mean gene expression was increased to 3.3-fold. An increase in muscle strength measurements and pulmonary function tests was detected. Additionally, we observed two of nine patients with positive panel reactive antigen result.ConclusionAll our procedures are well tolerated, and we have not seen any application-related complications so far. Our main purpose of this study was to investigate the effects of allogeneic mesenchymal stem cell therapy and determine its suitability and safety as a form of treatment in this untreatable disorder.

Therapies that are available and under development for Duchenne muscular dystrophy: What about lung function?

“…With regard to nonrandomized studies, the most significant sources of bias included bias due to confounding factors and bias in the selection of patients (preintervention) (Table ). More specifically, no adequate information about baseline traits of the participants was provided in a number of studies, different genetic background was not always considered by authors and patients included might have already received therapy (in different schedules) before recruitment to the study . In addition, in some cases the sample size was particularly small and only patients with the specific age of symptoms initiation were included .…”

“…We have identified 19 studies fulfilling our selection criteria [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] ( Figure 1): nine studies exploring the effect of steroids on pulmonary function, [17][18][19][20][21][22][23][24][25] six studies exploring the effect of idebenone (one study explored the effect of both steroids and idebenone), 19,[26][27][28][29][30] three studies about eteplirsen, [31][32][33] one study about ataluren, 34 and one study about stem-cell therapy 35 (Tables 1-3).…”

“…With regard to study design, 5 of 19 original research papers were retrospective studies 18,[22][23][24][25] and 13 were prospective studies, including six randomized controlled trials, 19,[26][27][28][29][30] four prospective studies with no control group, 20,21,34,35 three randomized controlled trials followed by an open-label phase, [31][32][33] and one prospective cohort study including a treatment and a nontreatment group. 17 It is noteworthy that in three studies the control group was a natural history cohort or a historical control group.…”

“…More specifically, no adequate information about baseline traits of the participants was provided in a number of studies, 20,21,25,35 different genetic background was not always considered by authors 18,23 and patients included might have already received therapy (in different schedules) before recruitment to the study. 18,22,23 In addition, in some cases the sample size was particularly small 20,22,34,35 and only patients with the specific age of symptoms initiation were included. 24 Furthermore, no specific details about methods of outcomes measurement were provided in a number of studies, 18,21,34 while in some other authors characterized differences as "moderate or serious" only by judgment without confirmation by statistical methods.…”

Duchenne’s Muscular Dystrophy: The Role of Induced Pluripotent Stem Cells and Genomic Editing on Muscle Regeneration

“…Duchenne's muscular dystrophy (DMD) is an X-linked recessive disorder, primarily affecting children around age four at an incidence of 1:5000 with an average life span of 30-40 years. DMD is due to a defect in the DMD gene encoding the dystrophin protein, which eventually leads to progressive muscle degeneration [ 1 , 2 ]. The dystrophin gene encodes typically for a functional dystrophin protein.…”