Acute intermittent porphyria: vector optimization for gene therapy

Yasuda, Makiko; Domaradzki, Maciej E.; Armentano, Donna; Cheng, Seng H.; Bishop, David F.; Desnick, Robert J.

doi:10.1002/jgm.1074

Cited by 6 publications

(2 citation statements)

References 28 publications

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“…All these data proffer some hope of cure for selected patients with severe forms of these diseases. To date, other therapeutic approaches, such as the infusion of recombinant porphobilinogen deaminase [49] or gene therapy have to be considered as experimental [29]; the latter approach has showed very good results in animal models of AIP, especially after the recent optimization of gene vectors [50].…”

Section: Prevention Of Attacksmentioning

confidence: 99%

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

2009

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The porphyrias are a heterogeneous group of metabolic diseases resulting from a variable catalytic defect of one of the eight enzymes involved in the heme biosynthesis pathway; they are mostly inherited diseases, but in some circumstances the metabolic disturbance may be acquired. The specific patterns of tissue overproduction (and hence accumulation and excretion) of toxic heme precursors, associated with each enzymatic deficiency, are responsible for the characteristic biochemical and clinical features of each of these diseases. Moreover, even in the presence of a specific inherited enzymatic defect, many different environmental factors (such as drugs, calorie restriction, hormones, sunlight exposition, infections, etc.) often play a key role in triggering the clinical expression of the various forms of porphyrias. The porphyrias are often misdiagnosed diseases, due their multiform clinical manifestations, able to mimic many other more common diseases. For this reason, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially for the forms presenting with acute and life-threatening clinical features. According to the clinical features, the porphyrias can be classified into neuropsychiatric (characterized by neurovisceral crises involving autonomic and central nervous system but also the liver and the kidney with possible consequences in terms of neurological, psychic, cardiac, respiratory, liver and kidney functions), dermatological (mostly presenting with cutaneous lesions due to photosensitivity), and mixed forms. From a strictly clinical point of view, porphyrias presenting with neurovisceral attacks are also referred as acute porphyrias: they are the object of the present review. An accurate diagnosis of acute porphyria requires knowledge and the use of correct diagnostic tools, and it is mandatory to provide a more appropriate therapeutic approach and prevent the use of potentially unsafe drugs, able to severely precipitate these diseases, especially in the presence of life-threatening symptoms. To date, availability of a relatively stable haem preparation (haem arginate) has significantly improved the treatment outcome of acute porphyric attacks, so the knowledge about the diagnosis and the management of these diseases may be relevant for physicians working in internal medicine, neurology and emergency units.

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Section: Prevention Of Attacksmentioning

confidence: 99%

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

2009

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“…In addition, although adenoviral vectors resulted in therapeutic HMB-synthase levels in experimental mice, its expression was transient, thus making them impractical for clinical applications [51]. Administration of recombinant adenoviral, AAV8-based andrecombinant AAV (rAAV) vectors in murine models containing the HMB-synthase complementary DNA, resulted in increased levels of hepatic HMB-synthase activity, inhibiting the phenobarbital-induced ALA and PBG accumulation and thus, indicating a potential for future gene therapy [51][52][53]. Finally, Johansson et al, 2003 and2002 showed in mammalian cells that non-viral gene delivery encoding HMB-synthase results in high expression of functional enzyme [54,55], suggesting enzymereplacement gene therapy as a feasible proposal.…”

Section: Acute Intermittent Porphyriamentioning

confidence: 99%

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Domvri¹,

Porpodis²,

Koffa³

et al. 2012

CGT

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Gene therapy is a fundamentally novel therapeutic approach that involves introducing genetic material into target cells in order to fight or prevent disease. A number of different strategies of gene therapy are tested at experimental and clinical levels, including: a) replacing a mutated gene that causes disease with a healthy copy of the gene, b) inactivating a mutated gene that its improper function causes pathogenesis, c) introducing a new gene coding a therapeutic compound to fight a disease, d) introducing to the target organ an enzyme converting an inactive pro-drug to its cytotoxic metabolite. In gene therapy, the transcriptional machinery of the patient is used to produce the active factor that exerts the intended therapeutic effect, ideally in a permanent, tissue-specific and manageable way. The liver is a major target for gene therapy, presenting inherited metabolic defects of single-gene etiology, but also severe multifactorial pathologies with limited therapeutic options such as hepatocellular carcinoma. The initial promising results from gene therapy strategies in liver diseases were followed by skepticism on the actual clinical value due to specificity, efficacy, toxicity and immune limitations, but are recently re-evaluated due to progress in vector technology and monitoring techniques. The significant amount of experimental data along with the available information from clinical trials are systematically reviewed here and presented per pathological entity. Finally, future perspectives of gene therapy protocols in hepatology are summarized.

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Physiological and tissue-specific vectors for treatment of inherited diseases

Toscano

Romero

Muñoz³

et al. 2010

Gene Ther

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After more than 1500 gene therapy clinical trials in the past two decades, the overall conclusion is that for gene therapy (GT) to be successful, the vector systems must still be improved in terms of delivery, expression and safety. The recent development of more efficient and stable vector systems has created great expectations for the future of GT. Impressive results were obtained in three primary immunodeficiencies and other inherited diseases such as congenital blindness, adrenoleukodystrophy or junctional epidermolysis bullosa. However, the development of leukemia in five children included in the GT clinical trials for X-linked severe combined immunodeficiency and the silencing of the therapeutic gene in the chronic granulomatous disease clearly showed the importance of improving safety and efficiency. In this review, we focus on the main strategies available to achieve physiological or tissue-specific expression of therapeutic transgenes and discuss the importance of controlling transgene expression to improve safety. We propose that tissue-specific and/or physiological viral vectors offer the best balance between efficiency and safety and will be the tools of choice for future clinical trials in GT of inherited diseases.

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Acute intermittent porphyria: vector optimization for gene therapy

Abstract: These studies support the use of a gene therapy vector containing the alpha1Me/alpha1ATp combination for preclinical studies of the efficacy and safety of liver-targeted gene therapy for AIP.

Cited by 6 publications

References 28 publications

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

Physiological and tissue-specific vectors for treatment of inherited diseases

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