Combating oncogene activation associated with retrovirus-mediated gene therapy of X-linked severe combined immunodeficiency

A successful gene therapy clinical trial that also encountered serious adverse effects has sparked extensive study and debate about the future directions for retrovirus-mediated interventions. Treatment of X-linked severe combined immunodeficiency with an oncoretrovirus harboring a normal copy of the gc gene was applied in two clinical trials, essentially curing 13 of 16 infants, restoring a normal immune system without the need for additional immune-related therapies. Approximately 3 years after their gene therapy, tragically, 3 of these children, all from the same trial, developed leukemia as a result of this experimental treatment. The current understanding of the mechanism behind this leukemogenesis involves three critical and cooperating factors, i.e., viral integration, oncogene activation, and the function of the therapeutic gene. In this review, we will explore the causes of this unwanted event and some of the possibilities for reducing the risk of its reoccurrence.

Hepatite C / Hepatitis C

It has been estimated that 3% of the world population is infected with the hepatitis C virus. Those who are blood product recipients or have been illicit drug users are at risk. Dental and medical procedures as well as tattooing and acupuncture are also risk factors. Chronic infection occurs in up to 85% of infected cases but they may remain without symptoms during years or even decades, and clinical presentation varies. Determination of anti-HCV in sera is a fairly sensitive tool for the diagnosis, and confirmation requires the identification of HCV-RNA. Staging of the liver disease as well as definition of its present activity can be graded by liver biopsy. The aim of treatment is to stop the progression of the hepatic disease by inhibiting viral replication. Due to the low therapeutic efficacy combined with important side-effects, the administration of interferon and ribavirin have specific indications and contraindications. Predictive factors of therapeutic response, particularly viral load and genotypes of HCV, are useful in the evaluation of patients.

Estima-se que cerca de 3% da população mundial esteja infectada pelo vírus da hepatite C. Todos os que receberam transfusão de sangue ou seus componentes e os usuários de drogas podem estar infectados. Procedimentos odontológicos, médicos, tatuagem ou acupuntura também constituem fatores de risco. A infecção se cronifica em até 85% dos indivíduos, com evolução assintomática durante anos ou décadas e apresentação clínica variada. Para o diagnóstico, a determinação do anti-VHC revela-se muito sensível e a confirmação se faz pela determinação do RNA-VHC no sangue; o estadiamento da doença e a avaliação da atividade inflamatória pela biópsia hepática. O tratamento objetiva deter a progressão da doença hepática através da inibição da replicação viral. Devido à baixa eficácia terapêutica aliada a importantes efeitos colaterais do interferon e da ribavirina, esses medicamentos encontram indicações e contra-indicações específicas. Vários fatores preditivos de resposta ao tratamento, principalmente a carga viral e o genótipo do VHC, mostram-se úteis na avaliação dos pacientes.

Efficient retrovirus-mediated transfer of cell-cycle control genes to transformed cells

The use of gene therapy continues to be a promising, yet elusive, alternative for the treatment of cancer. The origins of cancer must be well understood so that the therapeutic gene can be chosen with the highest chance of successful tumor regression. The gene delivery system must be tailored for optimum transfer of the therapeutic gene to the target tissue. In order to accomplish this, we study models of G1 cell-cycle control in both normal and transformed cells in order to understand the reasons for uncontrolled cellular proliferation. We then use this information to choose the gene to be delivered to the cells. We have chosen to study p16, p21, p53 and pRb gene transfer using the pCL-retrovirus. Described here are some general concepts and specific results of our work that indicate continued hope for the development of genetically based cancer treatments

Activity of chronic hepatitis correlation of clinical, biochemical and histological parameters in 32 cases.

Os Autores estudaram 32 casos de hepatites cronicas com diversos graus de atividade clinica, bioquimica e histologica. A etiologia foi predominantemente viral. Quinze parametros histologicos foram semiquantificados, pesquisando-se posteriormente, correlacao entre os graus obtidos e os valores sericos de ALT, AST, Gama-GT, bilirrubina total e gamaglobulina. Dos parametros histologicos, a proliferacao de ductos biliares e os plasmocitos nao se mostraram uteis para esta analise. Os niveis de bilirrubina total apresentam correlacao estatisticamente significante com 11 variaveis histologicas. Ambas as aminotransferases (ALT e AST) correlacionaram-se com a impressao geral de atividade histologica, sendo que a AST tambem se correlacionou com o grau de expansao portal e de necrose "em saco bocados". A ausencia de correlacoes significantes com gamaglobulina pode se dever a inclusao, neste estudo, de casos de hepatite cronica persistente e a ausencia de hepatites cronicas autoimunes