Perspectives on gene therapy for lysosomal storage diseases that affect hematopoiesis

Successful gene therapy for lysosomal storage diseases that involve the bone marrow and hematopoiesis is hindered by the hostile microenvironments created by these diseases and the irreversibility of the pathologic manifestations. Of the 40 lysosomal storage diseases, Gaucher disease type I, Niemann-Pick B, and mucopolysaccharidosis type I have hematopoietic involvement, are treatable by enzyme therapy, and respond to bone marrow transplantation. These storage diseases provide the basis for continued development of gene therapy.     

Perspectives on therapy with diphosphonates in non-malignant diseases

Diphosphonates inhibit bone resorption. This therapeutic effect found early recognition in the treatment of Paget's disease. The favorable long-term effect of the substance gives rise to a shorter therapy period. Due to increased fracture incidence as a result of osteoidosis observed under ethane-hydroxy diphosphomate (EHDP) administration, today amino-hydroxy-propylidine diphosphonate (APD) and dichloromethylene diphosphonate (clodronate) are preferred in the treatment of Paget's disease. Diphosphonates inhibit both osteoblasts and osteoclasts, thus being also used in the treatment of primary osteoporosis. Their efficacy in high-turnover osteoporosis in the form of monotherapy or within the framework of cyclical therapy schemes has been demonstrated by an increase in bone mass. Diphosphonates have played an important role in the therapy of steroid-induced osteoporosis. Prevention of osteopenic changes is of utmost significance: a prophylactic effect was demonstrated in immobilization osteoporosis. In prophylaxis, diphosphonates might also be applied in women after ovariectomy who had to undergo surgery before the menopause due to oncologic indications and in whom the administration of estrogens to prevent expected osteoporosis is contra-indicated. The favorable effect of diphosphonates on bone changes in Gaucher's disease implies an inhibition of macrophage-mediated bone resorption. The importance of this substance in orthopedics will further contribute to prevent ectopic ossification in hip endoprosthetics.     

腺相关病毒载体在肺疾病基因治疗中的应用

腺相关病毒（adeno-associated virus,AAV）载体具有安全性好、免疫原性低、能感染分裂细胞和非分裂细胞、能介导基因的长期稳定表达等优点。因此,作为一种基因导入系统,重组AAV载体在基因治疗的研究和开发中受到越来越多的关注和重视。本文着重就重组AAV载体在肺部疾病基因治疗中的应用以及改进重组AAV载体的策略作简要综述。     

Consideration of gene therapy for paediatric neurotransmitter diseases

Summary  The paediatric neurotransmitter diseases (PNDs) are a group of inborn errors of metabolism characterized by abnormalities of neurotransmitter synthesis or metabolism. Although some children may react favourably to neurotransmitter augmentation treatment, optimal response is not universal and other modes of treatment should be sought. The genes involved in many of the currently known monoamine PNDs have been utilized in pre-clinical and in phase I clinical trials in Parkinson disease (PD) and the basic principles could be applied to the therapy of PNDs with some modifications regarding the targeting and distribution of vectors. However, issues that go beyond neurotransmitter replacement are important considerations in PD and even more so in PNDs. Understanding the pathophysiology of PNDs including abnormal development resulting from the neurotransmitter deficiency will be critical for rational therapeutic approaches. Better animal models of PNDs are necessary to test gene therapy before clinical trials can be attempted. Competing interests: None declared Presented at the 2nd Pediatric Neurotransmitter Disease (PND) Association Symposium, ‘Medical Management of Pediatric Neurotransmitter Disorders: A Multidisciplinary Approach’, 18–19 July, 2008, Hyatt Dulles Hotel, Herndon, VA, USA.     

基因治疗在血液病中应用进展

随着人类对自身认识的不断深化 ,从人类解剖学开始 ,已经进入了细胞和分子病理生理学研究 ,特别是从基因水平上阐明人类遗传与疾病这一核心本质。基因治疗 (ｇｅｎｅｔｈｅｒａｐｙ)的最初含义是指遗传病的基因替代治疗 (ｇｅｎｅ ｒｅ ｐｌａｃｅｍｅｎｔｔｈｅｒａｐｙ) ,即将正常基因通过某种途径转入到由于该基因缺陷而患有某种遗传病的患者体内 ,并表达患者所缺陷的蛋白产物 ,从而达到治疗该遗传病的目的。随着生物医学理论与技术的深入发展 ,基因治疗的涵义也不断扩大 ,目前广义上的基因治疗是指在基因水平上进行活细胞遗传物质的改造…     

Development of lentiviral vectors for gene therapy for human diseases

Retroviral vectors derived from murine retroviruses are being used in several clinical gene therapy trials. Recently, progress has been made in the development of vectors based on the lentivirus genus of retroviruses, which ironically includes a major human pathogen, human immunodeficiency virus (HIV). As these vector systems for clinical gene transfer are developed, it is important to understand the rationale behind their design and development. This article reviews the fundamental features of retrovirus replication and of the elements necessary for development of a retroviral vector system, and it discusses why vector systems based on HIV or other lentiviruses have the potential to become important tools in clinical gene therapy. (Blood. 2000;95:2499-2504)     

Comparison of gene therapy strategies for treatment of liver diseases

Abstract   Liver-directed gene therapy can be aimed at replacing a missing gene product, overexpressing or ectopically expressing a gene product in the liver, generating proteins that are normally not produced in the liver (e.g. hormones, vaccines), down-regulating specific gene expression and targeted repair of genetic mutations. A common critical requirement for achieving these goals is the availability of efficient methods for transferring DNA and RNA into target organ in vivo . Both recombinant viruses and non-viral vectors are being explored for transferring nucleic acids to cells in vitro and in vivo . This review compares the characteristics of these vectors in the context of their potential application in liver-directed gene therapy for various inherited or acquired disorders.     

Vectors and target cells for gene therapy of blood diseases

Gene therapy is the introduction of genetic material into somatic cells in order to correct a genetic defect or provide a new therapeutic function. Since the advent of gene transfer technologies, hematopoietic stem cells and hematologic diseases have been the focus of intensive efforts: blood cells can be removed from the body easily and reintroduced following ex vivo manipulation. The major applications of gene therapy for hematologic diseases fall into four major categories: genetic marking of hematopoietic progenitor cells, replacement of a missing or defective gene in an inherited deficiency, gene therapy of neoplastic disorders, intracellular immunization against human immunodeficiency virus (HIV) infection or other viral disorders. This review summarizes the different methods used for gene delivery and focuses on target cells for hematologic diseases amenable to gene therapy.     

Human erythropoietin gene therapy for patients with chronic renal failure

Gene therapy holds a major promise. However, until now, this promise was fulfilled only in few cases, in rare genetic diseases. One very common clinical condition is anemia. Patients with anemia of chronic renal failure are treated with erythropoietin. The objective of this study was to develop a therapeutic platform for serum-secreted proteins like erythropoietin. We developed a tissue protein factory based on dermal cores (Biopump) harvested and implanted autologously. In this study, an adenovector was designed to express the human erythropoietin under the control of the cytomegalovirus (CMV) promoter. This vector transduced the harvested dermal cores ex vivo. The transduced cores were implanted, and erythropoietin and reticulocyte counts were measured. Dermal cores were harvested from 13 patients with chronic renal failure, and implantation was performed in 10. There were no significant drug-related side effects to this procedure. Erythropoietin serum levels increased significantly to therapeutic levels from day 1 after implantation reaching a peak during the first week of follow-up. The expression period was transient for up to 14 days. The rise of erythropoietin was followed by a transient significant increase in reticulocyte counts. The decrease of erythropoietin expression coincided with a significant dermal infiltrate of CD8 cytotoxic T cells. Antierythropoietin antibodies were not detected until day 90 following implantation. Implantation of dermal cores ex vivo transduced with human genes could eventually be used in the clinical setting to express therapeutic serum proteins. However, nonimmunogenic delivery system should be tested as gene vehicles.     

Perspectives for metabolomics in testosterone replacement therapy

Testosterone is the major circulating androgen in men but exhibits an age-related decline in the ageing male. Late-onset hypogonadism or androgen deficiency syndrome (ADS) is a 'syndromic' disorder including both a persistent low testosterone serum concentration and major clinical symptoms, including erectile dysfunction, low libido, decreased muscle mass and strength, increased body fat, decreased vitality or depressed mood. Given its unspecific symptoms, treatment goals and monitoring parameters, this review will outline the various uncertainties concerning the diagnosis, therapy and monitoring of ADS to date. Literature was identified primarily through searches for specific investigators in the PubMed database. No date or language limits were applied in the literature search for the present review. The current state of research, showing that metabolomics is starting to have an impact not only on disease diagnosis and prognosis but also on drug treatment efficacy and safety monitoring, will be presented, and the application of metabolomics to improve the clinical management of ADS will be discussed. Finally, the scientific opportunities presented by metabolomics and other -omics as novel and promising tools for biomarker discovery and individualised testosterone replacement therapy in men will be explored.     

肝脏疾病基因治疗中非病毒性载体的研究进展

目前大部分肝脏疾病(病毒性肝炎、自身免疫性肝病、先天性代谢性肝病、原发性肝癌等)在临床上尚无有效的根治方法,作为医学研究中热点课题的基因治疗能否应用于肝脏疾病,引起了许多学者的关注.     

The promise of gene therapy in gastrointestinal and liver diseases

Gene therapy consists of the transfer of genetic material to cells to achieve a therapeutic goal. In the field of gastroenterology and hepatology gene therapy has produced considerable expectation as a potential tool in the management of conditions that lack effective therapy including non-resectable neoplasms of the liver, pancreas and gastrointestinal tract, chronic viral hepatitis unresponsive to interferon therapy, liver cirrhosis, and inflammatory bowel disease.     

Effective gene therapy in an authentic model of Tay-Sachs-related diseases

Tay-Sachs disease is a prototypic neurodegenerative disease. Lysosomal storage of GM2 ganglioside in Tay-Sachs and the related disorder, Sandhoff disease, is caused by deficiency of beta-hexosaminidase A, a heterodimeric protein. Tay-Sachs-related diseases (GM2 gangliosidoses) are incurable, but gene therapy has the potential for widespread correction of the underlying lysosomal defect by means of the secretion-recapture cellular pathway for enzymatic complementation. Sandhoff mice, lacking the beta-subunit of hexosaminidase, manifest many signs of classical human Tay-Sachs disease and, with an acute course, die before 20 weeks of age. We treated Sandhoff mice by stereotaxic intracranial inoculation of recombinant adeno-associated viral vectors encoding the complementing human beta-hexosaminidase alpha and beta subunit genes and elements, including an HIV tat sequence, to enhance protein expression and distribution. Animals survived for >1 year with sustained, widespread, and abundant enzyme delivery in the nervous system. Onset of the disease was delayed with preservation of motor function; inflammation and GM2 ganglioside storage in the brain and spinal cord was reduced. Gene delivery of beta-hexosaminidase A by using adeno-associated viral vectors has realistic potential for treating the human Tay-Sachs-related diseases.     

乙型肝炎抗病毒治疗的前瞻

乙型肝炎易于转变成慢性，最终可能发展成为肝硬化及肝癌，严重威胁人民的健康。近年，抗乙型肝炎病毒（HBV）药物的研究进展较大，如核酸类似物不断发展，免疫调节药物的研究不断深入等。我国己批准拉米夫定、阿德福韦（adefovir，ADV）酯、恩替卡韦及聚乙二醇化干扰素（pegylated interferon，PEG—IFN）等新药用于治疗慢性乙型肝炎，临床医师有较多的选择，因而美国、欧洲、亚太地区及我国相继修订指导原则，为临床医师临床诊断时提供参考。对乙型肝炎的探索在不断进展，对有些问题的认识在不断深化。