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Michael Linden

Professor

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Research interests

The study of adeno-associated virus (AAV) has brought our laboratory to the intersection of basic virological, genetic and biochemical studies with translational efforts, both in the gene transfer arena and the newly evolving stem cell discipline. In addition, we have committed considerable efforts to the establishment of an AAV vector core, with particular emphasis on scientific and organizational issues that allow for an efficient and appropriate process in providing recombinant AAV to a number of collaborating laboratories. The biology of AAV and AAV-based vectors Adeno-associated viruses (AAVs) have been studied since the early 1960s. In contrast to other human DNA viruses it has become clear that there is no significant correlation between the widespread infection by AAV throughout the population and any known disease entity. Studies throughout the past several decades have led to an emerging view that AAV might have evolved a possibly optimal relationship with its host through a unique life style that allows the virus to only replicate in cells that are infected by other viruses, which by themselves are deleterious to the host cell. Through this dependency AAV might have overcome an apparent challenge to viral life cycles in general: on one hand viruses depend on their respective hosts for replication, on the other, most viruses hurt the hosts through their replication to various degrees. Through its dependency, AAV will only replicate in cells that are affected by the consequences of helper virus infection. Thus, if our findings from tissue culture studies can be extrapolated to the human host, infection by AAV could indeed be viewed as beneficial to the host in that cells that are infected by adenovirus, herpes viruses and possibly papilloma viruses will die as a result of AAV replication. In light of this aspect it is no surprise that the AAVs appear widespread throughout the vertebrate kingdom. Molecular aspects. Possibly one of the most intriguing aspects of AAV biology is that it is the only known eukaryotic virus with the unique ability to integrate site-specifically into the human genome (Berns and Linden, 1995; Linden and Berns, 2000; Linden et al., 1996, Dutheil and Linden, 2006). On this background our laboratory has been active for a number of years in efforts to elucidate the molecular mechanisms underlying AAV2 site-specific integration and, related to this mechanism, DNA replication (Ward et al., 2003; Ward et al., 2001; Ward and Linden, 2000). We have approached these questions from different angles, including the genetic characterization of the human target locus for site-specific integration (Dutheil et al., 2000; Dutheil et al., 2004), the biochemical characterization of the AAV Rep proteins that are responsible for all aspects of the AAV life cycle, including site-specific integration (Smith et al., 1999; Yoon et al., 2001; Yoon-Robarts et al., 2004; Yoon-Robarts and Linden, 2003) and, more recently, the biophysical/structural basis for Rep action (James et al., 2004; James et al., 2003). These efforts have led us to be among the first to define the structure of SF3 helicases, and, as a result, to conclude that these proteins that are frequently found in viruses such as papilloma and polyoma viruses, in fact belong to the AAA+ proteins, a broad family of ATPases that are associated with a variety of functions ranging from membrane fusion, protein degradation and now also functions that are relating to several viral mechanisms. These include, but are not limited to DNA replication and genome packaging. Based on these findings we are now actively engaged in dissecting the biochemical and structural determinants underlying the molecular mechanisms supported by these viral AAA+ (vAAA+) proteins. Recombinant AAV vector core. During the past years we have spent considerable efforts in establishing a viral vector core that generates and purifies recombinant AAV vectors followed by stringent quality control assessments. At this point these vectors are distributed to a range of collaborators that are actively engaged in gene transfer experiments. Our current gene transfer collaborations include studies on pancreatic islet transplants, liver-mediated gene delivery for a number of monogenic diseases such as lysosomal storage diseases, a program that is aimed at the developmental aspects of kidney disease as well as several additional exploratory projects in neurology, neuroscience and Ophthalmology. The underlying philosophy to our efforts is to provide our strength to programs and projects that are founded on long-term and in-depth experience in the disease and animal models by our preclinical and clinical collaborators. In summary, our ongoing studies on the biology of viruses and AAV in particular has provided us with the opportunity to study unique viral and cellular mechanisms and to become part of the efforts in developing strategies that might ultimately become components of future gene and cell-based therapies.

Research interests (short)

Virology; gene and cell therapies; stem cell biology; molecular biology; structural biology.

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

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