No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease caused by autosomal recessive defect in a-N-acetylglucosaminidase (NAGLU). In anticipation of a clinical gene therapy treatment for MPS IIIB in humans, we tested the rAAV9-CMV-hNAGLU vector administration to cynomolgus monkeys (n = 8) at 1E13 vg/kg or 2E13 vg/kg via intravenous injection. No adverse events or detectable toxicity occurred over a 6-month period. Gene delivery resulted in persistent global central nervous system and broad somatic transduction, with NAGLU activity detected at 2.9-12-fold above endogenous levels in somatic tissues and 1.3-3-fold above endogenous levels in the brain. Secreted rNAGLU was detected in serum. Low levels of preexisting anti-AAV9 antibodies (Abs) did not diminish vector transduction. Importantly, high-level preexisting anti-AAV9 Abs lead to reduced transduction in liver and other somatic tissues, but had no detectable impact on transgene expression in the brain. Enzyme-linked immunoabsorbent assay showed Ab responses to both AAV9 and rNAGLU in treated animals. Serum anti-hNAGLU Abs, but not anti-AAV9 Abs, correlated with the loss of circulating rNAGLU enzyme. However, serum Abs did not affect tissue rNAGLU activity levels. Weekly or monthly peripheral blood interferon-c enzyme-linked immunospot assays detected a CD4 + T-cell (Th-1) response to rNAGLU only at 4 weeks postinjection in one treated subject, without observable correlation to tissue transduction levels. The treatment did not result in detectable CTL responses to either AAV9 or rNAGLU. Our data demonstrate an effective and safe profile for systemic rAAV9-hNAGLU vector delivery in nonhuman primates, supporting its clinical potential in humans.

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The reversibility of neuropathic lysosomal storage diseases, including MPS IIIA, is a major goal in therapeutic development, due to typically late diagnoses and a large population of untreated patients. We used self-complementary adeno-associated virus (scAAV) serotype 9 vector expressing human N-sulfoglucosamine sulfohydrolase (SGSH) to test the efficacy of treatment at later stages of the disease. We treated MPS IIIA mice at 1, 2, 3, 6, and 9 months of age with an intravenous injection of scAAV9-U1a-hSGSH vector, leading to restoration of SGSH activity and reduction of glycosaminoglycans (GAG) throughout the central nervous system (CNS) and somatic tissues at a dose of 5E12 vg/kg. Treatment up to 3 months age improved learning ability in the Morris water maze at 7.5 months, and lifespan was normalized. In mice treated at 6 months age, behavioral performance was impaired at 7.5 months, but did not decline further when retested at 12 months, and lifespan was increased, but not normalized. Treatment at 9 months did not increase life-span, though the GAG storage pathology in the CNS was improved. The study suggests that there is potential for gene therapy intervention in MPS IIIA at intermediate stages of the disease, and extends the clinical relevance of our systemic scAAV9-hSGSH gene delivery approach.

To date, little is known regarding the etiology and disease mechanisms of Alzheimer’s disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥2-fold, FDR≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson’s disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound ECM impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research.

Authors who have published in a subscription journal can do this by depositing the version of the article accepted for publication (version 2) in their own institution's repository.Os autores podem disponibilizar seus artigos em acesso aberto, arquivando, sem custo em um Repositório Institucional.Os autores que tiverem publicado em um periódico podem fazer isso pelo depósito da versão do artigo aceito para publicação (versão 2) no repositório da sua própria instituição. The impact of computer usage on scholarly communication among social scientists Sely Costa and Jack MeadowsLoughborough University, UK Received 17 December 1999 Abstract.An examination has been made of the effects of using information technology on the communication of research by social scientists in Brazil. Two disciplines were studiedeconomics and sociology -via both interviews and a questionnaire survey. A small sample of UK social scientists was also interviewed. The results indicate that major changes in communication habits are occurring. These are already well advanced for informal communication and are beginning to appear for formal communication.Differences have been found between economists and sociologists, with the former more active in their use of electronic facilities. Along with such discipline-related differences, the developments also appear to be influenced, in part, by pressures from the research community and from the institutional environment. One significant impact of information technology seems to be an increasing democratisation of the international research community.

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The relative information content of titles of research papers in different subject areas has been examined by counting the number of their ‘substantive’ words in eleven English periodicals, two French and two German. Chemistry and botany (in which KWIC indexes are already produced) are found to have the highest values, followed by physics, medicine, history, and the social sciences, with philosophy lowest. The information content of the foreign titles when translated into English was almost equal to that of English titles in the same subjects. Most subjects showed a significant increase in the number of substantive words between 1947 and 1973. Some difficulties of searching by title due to the vocabularies of non‐scientific subjects are discussed.

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