Systemic cell therapy for muscular dystrophies

Abstract

The intrinsic regenerative capacity of skeletal muscle makes it an excellent target for cell therapy. However, the potential of muscle tissue to renew is typically exhausted and insufficient in muscular dystrophies (MDs), a large group of heterogeneous genetic disorders showing progressive loss of skeletal muscle fibers. Cell therapy for MDs has to rely on suppletion with donor cells with high myogenic regenerative capacity. Here, we provide an overview on stem cell lineages employed for strategies in MDs, with a focus on adult stem cells and progenitor cells resident in skeletal muscle. In the early days, the potential of myoblasts and satellite cells was explored, but after disappointing clinical results the field moved to other muscle progenitor cells, each with its own advantages and disadvantages. Most recently, mesoangioblasts and pericytes have been pursued for muscle cell therapy, leading to a handful of preclinical studies and a clinical trial. The current status of (pre)clinical work for the most common forms of MD illustrates the existing challenges and bottlenecks. Besides the intrinsic properties of transplantable cells, we discuss issues relating to cell expansion and cell viability after transplantation, optimal dosage, and route and timing of administration. Since MDs are genetic conditions, autologous cell therapy and gene therapy will need to go hand-in-hand, bringing in additional complications. Finally, we discuss determinants for optimization of future clinical trials for muscle cell therapy. Joined research efforts bring hope that effective therapies for MDs are on the horizon to fulfil the unmet clinical need in patients. Graphical abstract

How Can Proteomics Help to Elucidate the Pathophysiological Crosstalk in Muscular Dystrophy and Associated Multi-System Dysfunction?

“…Besides testing novel pharmacological strategies [ 257 , 381 , 382 , 383 , 384 ] and immunomodulatory interventions [ 355 , 356 , 357 , 358 , 364 ], a variety of innovative therapeutic approaches are currently evaluated in the field of muscular dystrophy [ 385 , 386 , 387 , 388 , 389 ], including exon skipping [ 148 , 390 , 391 , 392 , 393 ], genomic editing [ 394 , 395 , 396 ], codon read-through [ 397 ], gene replacement with the help of adeno-associated viral vectors [ 398 , 399 , 400 , 401 , 402 ], dystrophin substitution with its autosomal homolog utrophin [ 403 , 404 , 405 ], and muscle stem cell therapy [ 406 , 407 , 408 , 409 ]. Hence, for the optimum pre-clinical testing of new therapies, the clinical evaluation of diverse patient cohorts during the various phases of clinal studies/trials, and long-term therapeutic monitoring, robust and specific biomarkers for the routine screening of the status of dystrophic patients are required [ 144 , 264 , 265 , 410 , 411 ].…”

Spinal Cord Organoids to Study Motor Neuron Development and Disease

“…However, their very limited proliferation capacity has not resulted in satisfactory clinical outcomes yet. Research into generating other muscle progenitors using hiPSC-derived muscle organoids, such as mesoangioblasts and pericytes, as well as at increasing their migration potential [ 177 ] once engrafted into the host tissue are ongoing [ 178 ]. Immune cells, together with MSCs and NPCs, have been a main subject of cell therapy trials due to their immunosuppressor or immunomodulation capabilities and the impact of these in neuronal death upon acute brain damage or in NDs.…”

Duchenne muscular dystrophy disease severity impacts skeletal muscle progenitor cells systemic delivery

“…Cell-based therapies were proposed for DMD by transplantation of myoblasts in which the enthusiasm of restoring dystrophin in the mdx mouse model by intra-muscular (IM) myoblast transplantation, resulted in 4 clinical trials in humans, that ultimately all failed to restore sufficient dystrophin to provide functional benefit ( Partridge et al, 1989 ; Law et al, 1991 ; Gussoni et al, 1992 ; 1997 ; Huard et al, 1992 ; Karpati et al, 1993 ; Miller et al, 1997 ). The systemic delivery of various myogenic cell types to DMD muscles have been reported including mesoangioblasts, DLL4 and PDGF-BB treated satellite cells, skeletal muscle-derived CD133+ cells, and induced Pax3 embryonic stem cell derived cells among others ( Guttinger et al, 2006 ; Sampaolesi et al, 2006 ; Darabi et al, 2008 ; Tedesco et al, 2011 ; Sitzia et al, 2016 ; Gerli et al, 2019 ; Ausems et al, 2021 ). An overlooked parameter in developing systemic cell therapeutics is the context of disease severity and the diseased microenvironment.…”