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Gene therapy makes islets from liver, treats diabetes

Development of Gene Therapy for Neurological Disorders

Abstract: Given improvements in viral vector design, production and efficiency of transduction in the central nervous system (CNS), as well as increased knowledge of neuropathological mechanisms in neurological disorders, success in treating a CNS disorder with gene transfer seems inevitable. Several different vector systems have been studied extensively and the adeno-associated viral vector system has been utilized in most early stage clinical trials in neurological disorders. Other vector systems, such as lentivirus, adenovirus, and herpes simplex virus are also viable vector platforms that should fill significant clinical niches based on their specific characteristics. In addition to the choice of the appropriate vector, the proper choice of transgene for the appropriate strategy to treat a neurological disorder is also critical. The example of glial cell line-derived neurotrophic factor ligands to treat Parkinson's disease is used to illustrate the importance of the interface between interpretation of pre-clinical data and consideration of the natural history of the disorder. This interface dictates the proper design of clinical trials that are capable of testing whether the treatment is actually successful. ... Read more

Viral delivery vectors for small interfering RNA

Since it was reported last year that double stranded RNA (dsRNA) could silence the expression of a specific gene by digesting the mRNA (1), it has been further revealed that small interfering RNA (siRNA) mediated RNA interference (RNAi) is a process conserved among plants, invertebrates, and vertebrates. RNAi has become a powerful tool for genetic analysis and gene silencing. In order to apply RNAi to mammalian systems, transfection of either synthetic oligonucleotides or plasmids has been a popular methodology. However, the technique is limited to specific cell lines and is nearly impossible in primary cells. Due to their small size ... Read more

Adenoviral vector and tumor specific replication

The application of adenoviral (Ad) vectors for cancer gene therapy moved one step forward in lieu of recent advances in related fields. These include the observation that several human tumor cell lines support the DNA replication in AdE1-, a deficient adenovirus with E1A and E1B deletions (1), and the development of an Ad E1-based vector that employs homologous recombination between inverted repeats to activate target genes (2).

Based on the above observation and development, Dr. Lieber and colleagues developed a new Ad vector. In this vector, the alkaline phosphatase (Ap) and E1A genes were cloned downstream of RSV (Rous sarcoma virus) ... Read more

Islet-derived progenitor cell transplantation helps diabetes patients

A team led by Dr. Edmond A. Ryan of the University of Alberta, Admonton, Alberta, Canada reported in Diabetes this month (51:2148-2157, Jul. 2002) the results of a small clinical trial of treatment of autoimmune type 1 diabetes by islet cell transplantation.

Seventeen patients who received the transplantation were followed up for an average of 20 months. Of the 15 patients who have been followed for at least one year, 9 (60%) no longer need to take insulin. Of the 6 patients who have been followed for at least 2 years, 4 (67%) are off insulin. The transplantations are of an ... Read more

Novel Methods of Type 1 Diabetes Treatment

Abstract: Type 1 diabetes is an autoimmune disease characterized by the cell-mediated destruction of insulin-producing β-cells, leading to impaired glucose homeostasis, insulin insufficiency, and other complications. Although classic genetic studies have linked numerous genes to the susceptibility of developing diabetes, the mechanisms by which they influence the disease course remain poorly understood. Epigenetics, inheritable changes in gene expression that occur without accompanying genetic mutation, can both serve as a link between the environment and genetic causes of disease and help explain some of the observed vagaries of diabetes. Elucidation of the epigenetic landscape as it relates to putative treatment modalities is highly warranted. Drugs with histone deacetylase activity are in clinical trials for cancer and certain inflammatory diseases with high safety profiles and they hold similar promise for amelioration of type 1 diabetes with diminished secondary complications. Full-fledged studies on the epigenetics of type 1 diabetes are highly likely to provide novel tools for the manipulation of the disease in the years to come. In this review, epigenetic regulation mediated by small molecular inhibitors of histone deacetylases and their potential for preventing diabetes are discussed. Insights into the nature of the genetic mechanisms unraveled by these studies are also highlighted. ... Read more

Mesenchymal Stem Cell-Based Therapy for Type 1 Diabetes

Abstract: Diabetes has increasingly become a worldwide health problem, causing huge burden on healthcare system and economy. Type 1 diabetes (T1D), traditionally termed "juvenile diabetes" because of an early onset age, is affecting 5~10% of total diabetic population. Insulin injection, the predominant treatment for T1D, is effective to ameliorate the hyperglycemia but incompetent to relieve the autoimmunity and to regenerate lost islets. Islet transplantation, an experimental treatment for T1D, also suffers from limited supply of human islets and poor immunosuppression. The recent progress in regenerative medicine, especially stem cell therapy, has suggested several novel and potential cures for T1D. Mesenchymal stem cell (MSC) based cell therapy is among one of them. MSCs are a type of adult stem cells residing in bone marrow, adipose tissue, umbilical cord blood, and many other tissues. MSCs, with self-renewal potential and transdifferentiation capability, can be expanded in vitro and directed to various cell lineages with relatively less efforts. MSCs have well-characterized hypoimmunogenicity and immunomodulatory effect. All these features make MSCs attractive for treating T1D. Here, we review the properties of MSCs and some of the recent progress using MSCs as a new therapeutic in the treatment of T1D. We also discuss the strength and limitations of using MSC therapy in human trials. ... Read more

Innovative Approaches for Enhancing Cancer Gene Therapy

Abstract: Gene therapy provides a novel platform for therapeutic intervention of several genetic and non-genetic disorders. With the recent developments in the field, a wide variety of viral and non-viral vectors have emerged that can deliver genetic payloads to target cells. However, non-targeted delivery of transgenes often results in undesirable effects, low tumor transduction, and reduced therapeutic index. In this review, we focus on some of the novel approaches that can be used to meet the present challenges in the field and translate the potential of cancer gene therapy from 'bench to bedside' in the near future. ... Read more

Recent Gene Therapy Advancements for Neurological Diseases

Abstract: The past few years have seen rapid advancements in vector-mediated gene transfer to the nervous system and modest successes in human gene therapy trials. The purpose of this review is to describe commonly-used viral gene transfer vectors and recent advancements towards producing meaningful gene-based treatments for central nervous system (CNS) disorders. Gene therapy trials for Canavan disease, Batten disease, adrenoleukodystrophy, and Parkinson's disease are discussed to illustrate the current state of clinical gene transfer to the CNS. Preclinical studies are under way for a number of diseases, primarily lysosomal storage disorders, using a newer generation of vectors and delivery strategies. Relevant studies in animal models are highlighted for Mucopolysaccharidosis IIIB and Krabbe disease to provide a prelude for what can be expected in the coming years for human gene transfer trials, using recent advancements in gene transfer technology. In conclusion, recent improvements in CNS gene transfer technology are expected to significantly increase the degree of disease rescue in future CNS-directed clinical trials, exceeding the modest clinical successes that have been observed so far. ... Read more

Closed-loop Insulin Delivery: Towards Improved Diabetes Care

Abstract: The prevalence of type 1 diabetes is escalating worldwide. Novel therapies and management strategies are needed to reduce associated morbidity. Aggressive blood glucose lowering using conventional insulin replacement regimens is limited by the risk of hypoglycemia. Even the most motivated patients may struggle to manage day-to-day variability in insulin requirements. The artificial pancreas or closed-loop insulin delivery may improve outcomes, building on recent technological progress and combining continuous glucose monitoring with insulin pump therapy. So far, closed-loop prototypes have been evaluated under controlled conditions suggesting improved glucose control and a reduced risk of hypoglycemia. Limitations include suboptimal accuracy and reliability of continuous glucose monitors and delays associated with subcutaneous insulin delivery. Outpatient evaluation is required as the next step, leading to deployment into clinical practice. ... Read more

The Interplay of Autoimmunity and Insulin Resistance in Type 1 Diabetes

Abstract: Type 1 diabetes (T1D) is a common chronic disease characterized by selective autoimmune destruction of the pancreatic islet beta cells and subsequent dependence on exogenous insulin. Certain alleles including the high-risk HLA genotype, HLA-DR3-DQ2/DR4-DQ8, place individuals at increased risk of developing T1D. Autoantibodies to beta cell antigens are used in the diagnosis of T1D, and studies have shown that they can be used to predict risk of developing T1D in first degree relatives of probands. The annual global incidence of T1D is increasing by 3-5% per year. Many environmental factors have been implicated in the rising incidence of T1D. Proponents of the accelerator hypothesis argue that T1D and type 2 diabetes (T2D) are the same disorder of insulin resistance, although with different genetic backgrounds. While insulin resistance is a recognized hallmark of T2D, it also appears to play a significant role in the pathogenesis of T1D and its vascular complications. In this article, we will review: 1) immunogenetics of T1D, 2) risk factors for the development of islet autoimmunity and T1D, 3) mechanisms of insulin resistance in T1D, and 4) links between insulin resistance and complications in T1D. Further studies are needed to define environmental factors causing T1D as well as the role of insulin resistance in the pathogenesis of T1D and its complications. ... Read more

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