A novel adeno-associated virus capsid with enhanced neurotropism corrects a lysosomal transmembrane enzyme deficiency.
Brain. 2018 May 16;:
Authors: Tordo J, O'Leary C, Antunes ASLM, Palomar N, Aldrin-Kirk P, Basche M, Bennett A, D'Souza Z, Gleitz H, Godwin A, Holley RJ, Parker H, Liao AY, Rouse P, Youshani AS, Dridi L, Martins C, Levade T, Stacey KB, Davis DM, Dyer A, Clément N, Björklund T, Ali RR, Agbandje-McKenna M, Rahim AA, Pshezhetsky A, Waddington SN, Linden RM, Bigger BW, Henckaerts E
Recombinant adeno-associated viruses (AAVs) are popular in vivo gene transfer vehicles. However, vector doses needed to achieve therapeutic effect are high and some target tissues in the central nervous system remain difficult to transduce. Gene therapy trials using AAV for the treatment of neurological disorders have seldom led to demonstrated clinical efficacy. Important contributing factors are low transduction rates and inefficient distribution of the vector. To overcome these hurdles, a variety of capsid engineering methods have been utilized to generate capsids with improved transduction properties. Here we describe an alternative approach to capsid engineering, which draws on the natural evolution of the virus and aims to yield capsids that are better suited to infect human tissues. We generated an AAV capsid to include amino acids that are conserved among natural AAV2 isolates and tested its biodistribution properties in mice and rats. Intriguingly, this novel variant, AAV-TT, demonstrates strong neurotropism in rodents and displays significantly improved distribution throughout the central nervous system as compared to AAV2. Additionally, sub-retinal injections in mice revealed markedly enhanced transduction of photoreceptor cells when compared to AAV2. Importantly, AAV-TT exceeds the distribution abilities of benchmark neurotropic serotypes AAV9 and AAVrh10 in the central nervous system of mice, and is the only virus, when administered at low dose, that is able to correct the neurological phenotype in a mouse model of mucopolysaccharidosis IIIC, a transmembrane enzyme lysosomal storage disease, which requires delivery to every cell for biochemical correction. These data represent unprecedented correction of a lysosomal transmembrane enzyme deficiency in mice and suggest that AAV-TT-based gene therapies may be suitable for treatment of human neurological diseases such as mucopolysaccharidosis IIIC, which is characterized by global neuropathology.
PMID: 29788236 [PubMed - as supplied by publisher]
Impedance-based cellular assays for regenerative medicine.
Philos Trans R Soc Lond B Biol Sci. 2018 Jul 05;373(1750):
Authors: Gamal W, Wu H, Underwood I, Jia J, Smith S, Bagnaninchi PO
Therapies based on regenerative techniques have the potential to radically improve healthcare in the coming years. As a result, there is an emerging need for non-destructive and label-free technologies to assess the quality of engineered tissues and cell-based products prior to their use in the clinic. In parallel, the emerging regenerative medicine industry that aims to produce stem cells and their progeny on a large scale will benefit from moving away from existing destructive biochemical assays towards data-driven automation and control at the industrial scale. Impedance-based cellular assays (IBCA) have emerged as an alternative approach to study stem-cell properties and cumulative studies, reviewed here, have shown their potential to monitor stem-cell renewal, differentiation and maturation. They offer a novel method to non-destructively assess and quality-control stem-cell cultures. In addition, when combined with in vitro disease models they provide complementary insights as label-free phenotypic assays. IBCA provide quantitative and very sensitive results that can easily be automated and up-scaled in multi-well format. When facing the emerging challenge of real-time monitoring of three-dimensional cell culture dielectric spectroscopy and electrical impedance tomography represent viable alternatives to two-dimensional impedance sensing.This article is part of the theme issue 'Designer human tissue: coming to a lab near you'.
PMID: 29786561 [PubMed - in process]
Decreasing recurrent bowel obstructions, improving quality of life with physiotherapy: Controlled study.
World J Gastroenterol. 2018 May 21;24(19):2108-2119
Authors: Rice AD, Patterson K, Reed ED, Wurn BF, Robles K, Klingenberg B, Weinstock LB, Pratt JS, King CR, Wurn LJ
AIM: To compare (1) quality of life and (2) rate of recurrent small bowel obstructions (SBO) for patients treated with novel manual physiotherapy vs no treatment.
METHODS: One hundred and three subjects (age 19-89) with a history of recurrent adhesive SBO were treated with a manual physiotherapy called the Clear Passage Approach (CPA) which focused on decreasing adhesive crosslinking in abdominopelvic viscera. Pre- and post-therapy data measured recurring obstructions and quality of life, using a validated test sent 90 d after therapy. Results were compared to 136 untreated control subjects who underwent the same measurements for subjects who did not receive any therapy, which is the normal course for patients with recurring SBO. Comparison of the groups allowed us to assess changes when the physiotherapy was added as an adjunct treatment for patients with recurring SBO.
RESULTS: Despite histories of more prior hospitalizations, obstructions, surgeries, and years impacted by bowel issues, the 103 CPA-treated subjects reported a significantly lower rate of repeat SBO than 136 untreated controls (total obstructions P = 0.0003; partial obstructions P = 0.0076). Subjects treated with the therapy demonstrated significant improvements in five of six total domains in the validated Small Bowel Obstruction Questionnaire (SBO-Q). Domains of diet, pain, gastrointestinal symptoms, quality of life (QOL) and pain severity when compared to post CPA treatment were significantly improved (P < 0.0001). The medication domain was not changed in the CPA treated group (P = 0.176).
CONCLUSION: CPA physical therapy was effective for patients with adhesive SBO with significantly lower recurrence rate, improvement in reported symptoms and overall quality of life of subjects.
PMID: 29785079 [PubMed - in process]
[Preparation of borneol loaded hollow mesoporous silica nanoparticles and effect on borneol volatility].
Zhongguo Zhong Yao Za Zhi. 2016 Aug;41(15):2809-2813
Authors: Wang HY, Zhou F, Yu MM, Jin XH
The hollow mesoporous silica nanoparticles (HMSNs) were prepared by hard template method, with a size of 300 nm and shell thickness of 25 nm. Borneol was loaded with solvent impregnation method in order to solve the stability problem of borneol in pharmaceutics, and the BET, TEM and FT-IR were used to characterize the HMSNs and the borneol-HMSNs drug delivery system. The optimal drug loading time, maximum drug loading capacity and the volatility of borneol were investigated. The results showed that HMSNs which were prepared at room temperature and neutral conditions had good sphericity, achieved high drug loading of borneol in a short time, and the drug loading was up to 74.04% within 6 hours; meanwhile, volatility of borneol in the system was greatly improved. This novel drug delivery system provides a new idea for wide application of borneol in the traditional Chinese medicine.
PMID: 28914020 [PubMed - indexed for MEDLINE]
A novel classification method for aid decision of traditional Chinese patent medicines for stroke treatment.
Front Med. 2017 Sep;11(3):432-439
Authors: Zhao Y, Liu B, He L, Bai W, Yu X, Cao X, Luo L, Rong P, Zhao Y, Li G, Liu B
Traditional Chinese patent medicines are widely used to treat stroke because it has good efficacy in the clinical environment. However, because of the lack of knowledge on traditional Chinese patent medicines, many Western physicians, who are accountable for the majority of clinical prescriptions for such medicine, are confused with the use of traditional Chinese patent medicines. Therefore, the aid-decision method is critical and necessary to help Western physicians rationally use traditional Chinese patent medicines. In this paper, Manifold Ranking is employed to develop the aid-decision model of traditional Chinese patent medicines for stroke treatment. First, 115 stroke patients from three hospitals are recruited in the cross-sectional survey. Simultaneously, traditional Chinese physicians determine the traditional Chinese patent medicines appropriate for each patient. Second, particular indicators are explored to characterize the population feature of traditional Chinese patent medicines for stroke treatment. Moreover, these particular indicators can be easily obtained byWestern physicians and are feasible for widespread clinical application in the future. Third, the aid-decision model of traditional Chinese patent medicines for stroke treatment is constructed based on Manifold Ranking. Experimental results reveal that traditional Chinese patent medicines can be differentiated. Moreover, the proposed model can obtain high accuracy of aid decision.
PMID: 28500428 [PubMed - indexed for MEDLINE]