The motor system controls muscle movement through lower motor neurons in the spinal cord and brainstem. Lower motor neurons are efferent neurons in the central nervous system (CNS) characterized by axonal projections that reach specific targets in the periphery. Lower motor neuron lesions result in the denervation and dysfunction of peripheral skeletal muscle. Great progress has been made to develop therapeutic strategies to transduce lower motor neurons with genes. However, the widespread distribution of lower motor neurons makes their specific, extensive, and efficient transduction a challenge. In this study, we demonstrated that, compared to the other tested recombinant adeno-associated virus (rAAV) serotypes, rAAV2-retro mediated the most efficient retrograde transduction of lower motor neurons in the spinal cord following intramuscular injection in neonatal mice. A single injection of rAAV2-retro in a single muscle enabled the efficient and extensive transduction of lower motor neurons in the spinal cord and brainstem rather than transducing only the lower motor neurons connected to the injected muscle. rAAV2-retro achieved the extensive transduction of lower motor neurons by the cerebrospinal fluid pathway. Our work suggests that gene delivery via the intramuscular injection of rAAV2-retro represents a promising tool in the development of gene therapy strategies for motor neuron diseases.
In cardiac tissue engineering, myocardial surface patches and hydrogel intramyocardial injections represent the two primary hydrogel-based strategies for myocardial infarction (MI) treatment. However, the comparative effectiveness of these two treatments remains uncertain. Therefore, this study aimed to compare the effects of the two treatment modalities by designing a simple and reproducible hydrogel cross-linked with γ-PGA and 4-arm-PEG-SG. To improve mitochondrial damage in cardiomyocytes (CMs) during early MI, we incorporated the mitochondria-targeting antioxidant MitoQ into the hydrogel network. The hydrogel exhibited excellent biodegradability, biocompatibility, adhesion, and injectability in vitro. The hydrogel was utilized for rat MI treatment through both patch adhesion and intramyocardial injections. In vivo results demonstrated that the slow release of MitoQ peptide from the hydrogel hindered ROS production in CM, alleviated mitochondrial damage, and enhanced CM activity within 7 days, effectively inhibiting MI progression. Both hydrogel intramyocardial injections and patches exhibited positive therapeutic effects, with intramyocardial injections demonstrating superior efficacy in terms of cardiac function and structure in equivalent treatment cycles. In conclusion, we developed a MitoQ/hydrogel system that is easily prepared and can serve as both a myocardial patch and an intramyocardial injection for MI treatment, showing significant potential for clinical applications.
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