Low efficacy of recombinant SV40 in Ugt1a1-/- mice with severe inherited hyperbilirubinemia

In contrast to AAV, Simian Virus 40 (rSV40) not inducing neutralizing antibodies (NAbs) allowing re-treatment seems a promising vector for neonatal treatment of inherited liver disorders. Several studies have reported efficacy of rSV40 in animal models for inherited liver diseases. In all studies the ubiquitous endogenous early promoter controlled transgene expression establishing expression in all transduced tissues. Restricting this expression to the target tissues reduces the risk of immune response to the therapeutic gene. In this study a liver specific rSV40 vector was generated by inserting a hepatocyte specific promoter. This increased the specificity of the expression of hUGT1A1 in vitro. However, in vivo the efficacy of rSV40 appeared too low to demonstrate tissue specificity while increasing the vector dose was not possible because of toxicity. In contrast to earlier studies, neutralizing antibodies were induced. Overall, the lack of a platform to produce high titered and pure rSV40 particles and the induction of NAbs, renders it a poor candidate for in vivo gene therapy.

The flavonoid 7,8-DHF fosters prenatal brain proliferation potency in a mouse model of Down syndrome

Neurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety. We previously found that neonatal treatment with 7,8-dihydroxyflavone (7,8-DHF), a flavonoid present in plants, restores hippocampal neurogenesis in the Ts65Dn model of DS. The goal of the current study was to establish whether prenatal treatment with 7,8-DHF improves/restores overall brain proliferation potency. Pregnant Ts65Dn females received 7,8-DHF from embryonic day 10 until delivery. On postnatal day 2 (P2) the pups were injected with BrdU and were killed after either 2 h or 52–60 days (P52–60). Evaluation of the number of proliferating (BrdU+) cells in various forebrain neurogenic niches of P2 mice showed that in treated Ts65Dn mice proliferation potency was improved or even restored in most of the examined regions, including the hippocampus. Quantification of the surviving BrdU+ cells in the dentate gyrus of P52–60 mice showed no difference between treated and untreated Ts65Dn mice. At P52–60, however, treated Ts65Dn mice exhibited a larger number of granule cells in comparison with their untreated counterparts, although their number did not reach that of euploid mice. Results show that 7,8-DHF has a widespread impact on prenatal proliferation potency in Ts65Dn mice and exerts mild long-term effects. It remains to be established whether treatment extending into the neonatal period can lead to an improvement in brain development that is retained in adulthood.

INDICAÇÕES TERAPÊUTICAS NA PARALISIA DE ERB-DUCHENNE NEONATAL: UMA REVISÃO BIBLIOGRÁFICA

INTRODUÇÃO: A paralisia de Erb-Duchenne é a mais frequente paralisia neonatal do plexo braquial, correspondendo a mais de 60% dos casos. A maioria dos indivíduos se recupera espontaneamente, porém existe uma parcela que possui déficits neurológicos e necessita de tratamentos específicos. Para o tratamento tem-se as medidas conservadoras, os procedimentos cirúrgicos convencionais e os complementares. Diante do prejuízo de qualidade de vida, da constância dos casos e da ausência de um protocolo que guie as escolhas terapêuticas da patologia, este estudo visa orientar a utilização de cada método de tratamento. METODOLOGIA: O estudo consistiu em uma revisão sistemática realizada por meio de consultas nas bases dados, Biblioteca Virtual de Saúde (BVS) e U.S National Library of Medicine (PubMed) utilizando os descritores "Erb-Duchenne", "neonatal", "treatment" e "plexus brachial". Ademais, a busca bibliográfica embasou-se em artigos científicos completos, nos idiomas inglês, português e espanhol, os quais tenham sido publicados nos últimos cinco anos. RESULTADOS: As opções de tratamento são definidas pela avaliação clínica e pelo tipo de lesão. É consenso que a medida conservadora seja iniciada precocemente. Ha três abordagens cirúrgicas principais: neurólise externa, enxerto de nervo e transferência de nervo. O uso de toxina botulínica A BTX-A também foi descrito e melhorou a função muscular e a postura anormal em todos os casos. Nesta perspectiva, houve aumento de ate 3 pontos na Escala de Movimento Ativo. DISCUSSÃO: Os estudos apresentam divergências no que se refere ás alternativas terapêuticas. Muitos evidenciam a relevância do acompanhamento multidisciplinar e a inclusão de técnicas complementares como a injeção de toxina botulínica. A BTX-A tem se mostrado eficaz e segura no tratamento de desequilíbrios musculares, contrações e contraturas musculares, podendo ser utilizada nesses pacientes. Sobre o tratamento cirúrgico destacam-se as cirurgias primarias, comumente indicadas para crianças que não apresentam nenhum tipo de recuperação espontânea dentro de um espectro entre três a noves meses; e as cirurgias secundárias, recomendadas para aqueles pacientes que, submetidos ou não a primaria, ainda apresentam déficits funcionais significativos. Procedimentos de salvamento podem ser realizados na infância tardia para melhorar quadros de sequela da doença. CONCLUSÃO: Ressalta-se a necessidade de mais estudos nesta área, a fim de se direcionar a seleção terapêutica de forma mais assertiva, no fito de se priorizar a reabilitação e recuperação dos bebês e crianças.

Prenatal Treatment of Congenital Cytomegalovirus With Valganciclovir: A Case Report

Cytomegalovirus (CMV) is the most common congenital infection and infectious cause of fetal anomaly and neurologic injury. However, treatment strategies for congenital CMV (cCMV) infection during pregnancy remain elusive. We report a case of hydrops fetalis secondary to cCMV infection with minimal sequelae after maternal and subsequent neonatal treatment with valganciclovir.

EFFECTIVENESS OF PHENYLKETONURIA DIAGNOSIS IN THE NEONATAL TREATMENT REFERENCE SERVICE

Phenylketonuria is an inborn error of metabolism of autosomal recessive inheritance, with partial or total deficiency of the phenylalanine hydroxylase hepatic enzyme, which converts L-phenylalanine into tyrosine, thus causing accumulation of phenylalanine at the brain and serum level, interfering in the brain protein synthesis and entailing serious deficits. The objective of this study was to analyze the effectiveness of Phenylketonuria Diagnosis in the neonatal treatment reference service. This is a cross-sectional, analytical study with a quantitative approach, documented with retrospective data collection. Sociodemographic data, diagnosis, onset of treatment and the coverage rate analysis were grouped on a quadrennial basis. The sample consisted of 14 patients, from whom 57.1% had records of birth and collection time. In variable days of life, 28.6% were screened within the recommended period, 71.4% were diagnosed up to one month of life and 1 case at 3 years of age, for the onset of treatment (14.3%). The ideal collection would be performed up to 30 days of life. The lowest coverage rate for quadrennial was between 2014-2017 with 84.3%, with an incidence of 1:21,933. In conclusion, we highlight the need to optimize the neonatal screening service in order to make early diagnosis, begin specific treatment and minimize or eradicate irreversible sequelae.