Ex Vivo Gene Therapy Treats Bone Complications of Mucopolysaccharidosis Type II Mouse Models through Bone Remodeling Reactivation

Mucopolysaccharidosis type II is a disease caused by organ accumulation of glycosaminoglycans due to iduronate 2-sulfatase deficiency. This study investigated the pathophysiology of the bone complications associated with mucopolysaccharidosis II and the effect of lentivirus-mediated gene therapy of hematopoietic stem cells on bone lesions of mucopolysaccharidosis type II mouse models in comparison with enzyme replacement therapy. Bone volume, density, strength, and trabecular number were significantly higher in the untreated mucopolysaccharidosis type II mice than in wild-type mice. Accumulation of glycosaminoglycans caused reduced bone metabolism. Specifically, persistent high serum iduronate 2-sulfatase levels and release of glycosaminoglycans from osteoblasts and osteoclasts in mucopolysaccharidosis type II mice that had undergone gene therapy reactivated bone lineage remodeling, subsequently reducing bone mineral density, strength, and trabecular number to a similar degree as that observed in wild-type mice. Bone formation, resorption parameters, and mineral density in the diaphysis edge did not appear to have been affected by the irradiation administered as a pre-treatment for gene therapy. Hence, the therapeutic effect of gene therapy on the bone complications of mucopolysaccharidosis type II mice possibly outweighed that of enzyme replacement therapy in many aspects.Wada M., Shimada Y., Iizuka S., et al. Ex Vivo Gene Therapy Treats Bone Complications of Mucopolysaccharidosis Type II Mouse Models through Bone Remodeling Reactivation. Molecular Therapy - Methods and Clinical Development, 19, 261. https://doi.org/10.1016/j.omtm.2020.09.012

TFEB overexpression promotes glycogen clearance of Pompe disease iPSC-derived skeletal muscle

Pompe disease (PD) is a lysosomal disorder caused by acid α-glucosidase (GAA) deficiency. Progressive muscular weakness is the major symptom of PD, and enzyme replacement therapy can improve the clinical outcome. However, to achieve a better clinical outcome, alternative therapeutic strategies are being investigated, including gene therapy and pharmacological chaperones. We previously used lentiviral vector-mediated GAA gene transfer in PD patient-specific induced pluripotent stem cells. Some therapeutic efficacy was observed, although glycogen accumulation was not normalized. Transcription factor EB is a master regulator of lysosomal biogenesis and autophagy that has recently been associated with muscular pathology, and is now a potential therapeutic target in PD model mice. Here, we differentiated skeletal muscle from PD patient-specific induced pluripotent stem cells by forced MyoD expression. Lentiviral vector-mediated GAA and transcription factor EB gene transfer independently improved GAA enzyme activity and reduced glycogen content in skeletal muscle derived from PD-induced pluripotent stem cells. Interestingly, GAA and transcription factor EB cooperatively improved skeletal muscle pathology, both biochemically and morphologically. Thus, our findings show that abnormal lysosomal biogenesis is associated with the muscular pathology of PD, and transcription factor EB gene transfer is effective as an add-on strategy to GAA gene transfer

Frequency of de novo mutations in Japanese patients with Fabry disease

We examined alpha-galactosidase A (GLA) gene mutations in 74 Japanese families with Fabry disease (FD) to determine the frequency of de novo mutations. In 5 of 74 families (6.8%), the probands had no positive family histories and were diagnosed as de novo because their parents had no mutations in GLA gene. The parents of Fabry patients do not necessarily have mutations in GLA gene which is an important consideration in genetic counseling for FD

Disease modeling and lentiviral gene transfer in patient-specific induced pluripotent stem cells from late-onset Pompe disease patient

Pompe disease is an autosomal recessive inherited metabolic disease caused by deficiency of acid α-glucosidase (GAA). Glycogen accumulation is seen in the affected organ such as skeletal muscle, heart, and liver. Hypertrophic cardiomyopathy is frequently seen in the infantile onset Pompe disease. On the other hand, cardiovascular complication of the late-onset Pompe disease is considered as less frequent and severe than that of infantile onset. There are few investigations which show cardiovascular complication of late onset Pompe disease due to the shortage of appropriate disease model. We have generated late-onset Pompe disease-specific induced pluripotent stem cell (iPSC) and differentiated them into cardiomyocytes. Differentiated cardiomyocyte shows glycogen accumulation and lysosomal enlargement. Lentiviral GAA rescue improves GAA enzyme activity and glycogen accumulation in iPSC. The efficacy of gene therapy is maintained following the cardiomyocyte differentiation. Lentiviral GAA transfer ameliorates the disease-specific change in cardiomyocyote. It is suggested that Pompe disease iPSC-derived cardiomyocyte is replicating disease-specific changes in the context of disease modeling, drug screening, and cell therapy

Visible-Light-Driven C−H Imidation of Arenes and Heteroarenes by a Phosphonium Ylide Organophotoredox Catalyst: Application to C−H Functionalization of Alkenes

Phosphonium ylide catalysis through an oxidative quenching cycle has been developed for visible-light-driven C−H imidation of arenes and heteroarenes. The present protocol could be applied not only to trihalomethylative lactonization reactions involving trifluoromethyl, trichloromethyl, and tribromomethyl radicals but also to the first example of an organophotoredox-catalyzed imidative lactonization reaction involving a nitrogen-centered electrophilic radical species

Successful Treatment of Recurrent Gastric Cancer with Chemotherapy for M ore than 6 Years : A Case Report

A 66 year-old male underwent a distal gastrectomy with D2 dissection in April 2003. Pathological findings showed a well-differentiated carcinoma with a depth of m, n2, stage II. Six months later, a computed tomography revealed multiple lymph node swellings in the para-aortic lesion ; we judged this to be a recurrence of the gastric cancer. As treatment, paclitaxel was administered weekly on days 1, 8, and 15, in combination with doxifluridine for 5 days per week, on a 28-day cycle. Following three courses of chemotherapy, the lymph nodes had almost disappeared. This therapy was continued until January 2007. Because of the appearance of a Virchow lymph node, S-1＋ cisplatin was administered. Following administration of the altered chemotherapy regime, a computed tomography displayed a significant reduction in Virchow lymph node swelling. Four years and ten months following the initiation of chemotherapy, the patient displayed jaundice. A computed tomography revealed lymph node swelling in the hepato-duodenal region. Following bile duct drainage, he received four cycles of paclitaxel and doxifluridine therapy. The patient then received S-1 monotherapy for 5 months. He died in February 2010, 6 years and 3 months after the recurrence in the stomach cancer

\u22Program designed by children\u22 as group psychotherapy for child with developmental difficulties

要約 1.想定されるグループの特徴 2.プログラム各論 4.プログラム立案の視点の総括本論文では，青年期の発達障害の子どもたちに対して行ったグループセラビーについて報告する。子どもたちが自ら遊びを企画しそれを他児と一緒に楽しむという「子ども企画プログラム」を実施した。子ども企画では，「自己表現」と「仲間との相互交流」の促進の2つを軸としてプログラムを作成している。1年間のプログラムとして，①導入（セラピストが企画した遊び）②子ども企画③心理劇を行った。具体的なプログラムの実施方法として目的やルール使用した道具などについて紹介する。企画する段階から子どもにとってのセラピーと捉え，子どもの自発性と他者配慮の能力のレベルに合わせて，セラピストは援助している。The purpose of this study was to consider the group psychotherapy program for the children with developmental difficulties, especially in adolescence. In the therapy, to promote children\u27s self expression and interactions between children, group leader made a program that is called \u22Program designed by children\u22. In this program, self-expression and mutual interaction with other children was important aspects. The programs applied during a year were; 1) play programmed by group leader. 2) Program designed by children, 3) Psychodrama. Each therapist supported child designing the program in considering the functional levels of child\u27s ability and their spontaneity. Some examples of program including the rules, tools used in the sessions were introduced in this paper