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2 results on '"Hodgetts, SI"'

1. Is Viral Vector Gene Delivery More Effective Using Biomaterials?

Author

Wang, Y, Bruggeman, KF, Franks, S, Gautam, V, Hodgetts, SI, Harvey, AR, Williams, RJ, Nisbet, DR, Wang, Y, Bruggeman, KF, Franks, S, Gautam, V, Hodgetts, SI, Harvey, AR, Williams, RJ, and Nisbet, DR

Abstract

Gene delivery has been extensively investigated for introducing foreign genetic material into cells to promote expression of therapeutic proteins or to silence relevant genes. This approach can regulate genetic or epigenetic disorders, offering an attractive alternative to pharmacological therapy or invasive protein delivery options. However, the exciting potential of viral gene therapy has yet to be fully realized, with a number of clinical trials failing to deliver optimal therapeutic outcomes. Reasons for this include difficulty in achieving localized delivery, and subsequently lower efficacy at the target site, as well as poor or inconsistent transduction efficiency. Thus, ongoing efforts are focused on improving local viral delivery and enhancing its efficiency. Recently, biomaterials have been exploited as an option for more controlled, targeted and programmable gene delivery. There is a growing body of literature demonstrating the efficacy of biomaterials and their potential advantages over other delivery strategies. This review explores current limitations of gene delivery and the progress of biomaterial-mediated gene delivery. The combination of biomaterials and gene vectors holds the potential to surmount major challenges, including the uncontrolled release of viral vectors with random delivery duration, poorly localized viral delivery with associated off-target effects, limited viral tropism, and immune safety concerns.

Published
2021

2. Complement and myoblast transfer therapy: donor myoblast survival is enhanced following depletion of host complement C3 using cobra venom factor, but not in the absence of C5.

Author

Hodgetts SI and Grounds MD

Subjects
Animals, Cell Survival drug effects, Cells, Cultured, Complement C3 metabolism, Complement C5 metabolism, Female, Humans, Immunohistochemistry, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Muscle, Skeletal physiopathology, Muscular Dystrophy, Duchenne therapy, Cell Transplantation methods, Complement C3 immunology, Complement C5 immunology, Complement Inactivator Proteins pharmacology, Elapid Venoms pharmacology, Muscle, Skeletal cytology
Abstract

Myoblast transfer therapy (MTT) is a potential cell therapy for myopathies such as Duchenne Muscular Dystrophy and involves the injection of cultured muscle precursor cells ('myoblasts') isolated from normal donor skeletal muscles into dystrophic host muscle. The failure of donor myoblast survival following MTT is widely accepted as being due to the immune response of the host. The role of complement as one possible mechanism for the initial, very rapid death of myoblasts following MTT was investigated. Donor male myoblasts were injected into the tibialis anterior (TA) muscles of female host mice that were: (i) untreated; (ii) depleted of C3 complement (24 h prior to MTT) using cobra venom factor (CVF); and/or (iii) deficient in C5 complement. Quantification of surviving male donor myoblast DNA was performed using the Y-chromosome specific (Y1) probe on slot blots for samples taken at 0 h, 1 h, 24 h, 1 week and 3 weeks after MTT. Peripheral depletion of C3 was confirmed using double immunodiffusion, and local depletion of C3 in host TA muscles was confirmed by immunostaining of muscle samples. Cobra venom factor treatment significantly increased the initial survival of donor myoblasts, but there was a marked decline in myoblast numbers after 1 h and little long-term benefit by 3 weeks. Strain specific variation in the immediate survival of donor male myoblasts following MTT in untreated C57BL/10Sn, DBA-1 and DBA-2 (C5-deficient) female hosts was observed. Cobra venom factor depletion of C3 increased initial donor male myoblast survival (approximately twofold at 0 h) in C57BL/10Sn and DBA-1 host mice and approximately threefold in DBA-2 hosts at 0 h and 1 h after MTT. The rapid and extensive number (approximately 90%) of donor male myoblasts in untreated DBA-2 mice (that lack C5) indicates that activation of the membrane attack complex (MAC) plays no role in this massive initial cell death. The observation that myoblast survival was increased in all mice treated with CVF suggests that CVF may indirectly enhance donor myoblast survival by a mechanism possibly involving activated C3 fragments.

Published
2001
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