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Enzymes for Prodrug-Activation in Cancer Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
The Glybera therapy designed as a one-time treatment is based on adeno-associated virus that delivers a functional copy of the LPL gene to skeletal muscle via intramuscular injection. The adenoviral vector serves as a carrier for the S447X variant (carried by 20% of the human population) of LPL. This mutation reduces the full-length LPL by one residue by substituting the codon for a terminal serine by a stop codon. S447X is a gain-of-function mutation; it not only decreased plasma TG but also increases high-density lipoprotein cholesterol (HDL-C) and reduces coronary artery disease risks (Ranganathan et al., 2012). In Glybera 96% of the AAV genome was replaced with the LPL gene, a promotor, and regulatory elements from other viruses, constituting the therapeutic DNA (Richards, 2012). Altogether alipogene tiparvovec with multiple rounds of applications faced rocky path to approval, last not least because the numbers of patients suffering from LPLD were too small to reach statistical significance (Libby and Wang, 2014, and literature cited therein).
Clinical Trials of Hematopoietic Stem Cells for Cardiac and Peripheral Vascular Diseases
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
We obtained -500 ml of marrow cells from each patient and isolated 2.8 × 109 to 0.7 × 109 MNC (1.6 × 109 cells [SD 0.6]), which included 9.6 × 107 to 0.84 × 107 CD34+ cells (3.7 × 107 [SD 1.8]). The BM-MNC were implanted by intramuscular injection into the gastrocnemius muscle of ischemic lower limbs (x40 sites) using a 26-gauge needle. Ankle-brachial index (ABI) values in BM-MNC-implanted limbs were increased by 0.1 (95% CI 0.07 to 0.12) from 0.37 [0.31 to 0.42] at baseline to 0.46 [0.40 to 0.52] at week 4 (P<0.0001). In contrast, PB-MNC-injected limbs showed much smaller increases in ABI (0.02 increase, 95% CI 0.01 to 0.024). In the follow-up study, improvement of ischemic status (ABI, tissue oxygen concentration, rest pain scale, pain-free walking time, improvement of ischemic ulcers) was maintained during 24-weeks of observation (Fig. 2) (see detail data in ref. 13). Angiography revealed a marked increase in visible collateral vessel numbers in 60% of patients (Fig. 3). Vessel numbers assessed by capillary/muscle fiber ratio (2.3 [SD 0.6]) were markedly increased compared with the contralateral saline-injected muscle (0.74 [0.31]) (Fig. 4A). CD31-positive endothelial cells express Ki-67 in the marrow-implanted limb (Fig. 4B). Ki-67 is a nuclear protein that is expressed in proliferating cells and nearly absent in normal vessels. No Ki-67 expression was detected in the saline-injected limb, suggesting the presence of proliferating endothelial cells in newly formed vessels.
Imaging of Intracellular Targets
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Electroporation in combination with hypothermia has been used in vivo for intracellular delivery of DNA/RNA (Aihara and Miyazaki 1998; Boutin et al. 2008), which could be translated to contrast agent delivery as well. Indeed, Leroy-Willig applied electroporation of rat tibialis muscle after local intramuscular injection of a plasmid coding for an MRI contrast agent. The amount of trapped contrast agent was determined for a range of electric field intensity (Leroy-Willig et al. 2005). They used a protocol proposed by Mir et al. which was developed for therapeutic gene transfer in mouse muscle and showed minimal adverse effects (Mir et al. 1999). A few years later, Holm et al. reported on its use for facilitated intracellular delivery of MRI contrast agent following systemic i.v. administration (Holm 2009). This study suggests that the contrast agent remains trapped for periods up to 2 months and this in concentrations high enough to allow for intracellular MRI imaging throughout this period.
Larger strength losses and muscle activation deficits in plantar flexors induced by backward downhill in reference to distance-matched forward uphill treadmill walk
Published in European Journal of Sport Science, 2018
Olivier Girard, Sébastien Banzet, Nathalie Koulmann, Mounir Chennaoui, Catherine Drogou, Hakim Chalabi, Sébastien Racinais
Based on MVC torque changes between before and 24-h post backward downhill walking in our previous study (Racinais et al., 2008), we estimated the required sample size at 10 participants with alpha of 0.05 and beta of 0.20 (i.e. power of 0.8, G*Power 3.1). Fourteen healthy male participants (mean ± SD; age 32 ± 4 years, body mass 78 ± 8 kg, stature 178 ± 5 cm) were included in the study. Participants declared 1-to-4 h physical activity in the week, with no important variation in the three months preceding the experiment, and were unaccustomed to eccentric exercise. Exclusion criteria were chronic or recent (≤2 weeks) treatment with drugs acting on skeletal muscle, recent (≤2 weeks) intramuscular injection, recent (≤3 months) history of traumatic muscle injury, contact sports practice (≥2 h/weeks). Experimental protocol was performed according to the Helsinki Declaration of 1975 as revised in 2008 on ethical principles for medical research involving human subjects. The project was approved by the Scientific Committee from Aspetar Orthopaedic and Sports Medicine Hospital and by the Ethics Committee of Shafallah Medical Genetics Center (Institutional Review Board – Project number 2011-003) in Doha, Qatar. Participants gave their informed, written consent prior to the commencement of the study, once the experimental procedures, associated risks, and potential benefits of participation had been explained.