publication

Adaptation of Humoral Memory

Immunological memory, as provided by antibodies, depends on the continued presence of antibody-secreting cells, such as long-lived plasma cells of the bone marrow. Survival niches for these memory plasma cells are limited in number. In an established immune system, acquisition of new plasma cells, generated in response to recent pathogenic challenges, requires elimination of old memory plasma cells. Here, we review the adaptation of plasma cell memory to new pathogens…

Local Biotech Startup Wants to Turn Body’s Cells Into Drug Factories

“It struck me that the way the body attacks a pathogen is similar to the way a computer attacks a password,” Scholz said. “You have this idea of immunity memory. If you get a vaccine, your body remembers it and suddenly the disease that used to kill you won’t even give you the sniffles. … So we really set about treating disease from an information-based perspective.”

Evaluating Risks of Insertional Mutagenesis by DNA Transposons in Gene Therapy

Investigational therapy can be successfully undertaken using viral- and nonviralmediated ex vivo gene transfer. Indeed, recent clinical trials have established the potential for genetically modified T cells to improve and restore health. Recently, the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to stably insert a chimeric antigen receptor (CAR) to redirect T-cell specificity…

High-Dose Enzyme Replacement Therapy in Murine Hurler Syndrome

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease that is systemic, including progressive neurodegeneration, mental retardation and death before the age of 10 years. MPS I results from defi- ciency of α-L-iduronidase (IDUA) in lysosomes and subsequent accumulation of glycosaminoglycans (GAG). Clinical enzyme replacement therapy (ERT) with intravenous laronidase reverses some aspects of MPS I disease…

Long-term In Vitro Correction of a-L-iduronidase Deficiency (Hurler Syndrome) in Human Bone Marrow

Allogeneic bone marrow transplantation is the most effective treatment for Hurler syndrome but, since this therapy is not available to all patients, we have considered an alternative approach based on transfer and expression of the normal gene in autologous bone marrow. A retroviral vector carrying the full-length cDNA for a-L-iduronidase has been constructed and used to transduce bone marrow from patients with this disorder…

Manufacture of Clinical-Grade CD19-Specific T Cells Stably Expressing Chimeric Antigen Receptor Using Sleeping Beauty System and Artificial Antigen Presenting Cells

Adoptive transfer of T cells expressing a CD19-specific chimeric antigen receptor (CAR) is being evaluated in multiple clinical trials. Our current approach to adoptive immunotherapy is based on a second generation CAR (designated CD19RCD28) that signals through a CD28 and CD3-f endodomain. T cells are electroporated with DNA plasmids from the Sleeping Beauty (SB) transposon/transposase system to express this CAR…

Manufacture of T Cells Using the Sleeping Beauty System to Enforce Expression of a CD19-Specific Chimeric Antigen Receptor

T cells can be reprogrammed to redirect specificity to tumor-associated antigens (TAAs) through the enforced expression of chimeric antigen receptors (CARs). The prototypical CAR is a single-chain molecule that docks with TAA expressed on the cell surface and, in contrast to the T-cell receptor complex, recognizes target cells independent of human leukocyte antigen…

Plasma Cells for a Lifetime?

Antigen-specific serum antibodies are protective for long periods of time. These serum antibodies, the “humoral memory”, are secreted by plasma cells derived from activated, antigen-specific B lymphocytes. Given their crucial role in immunity, surprisingly little is known about the biology of plasma cells. One of the fundamental questions is whether persisting protective serum antibody responses are maintained by long-lived plasma cells, or by short-lived plasma cells generated continuously from activated memory B cells…

Prolonged Expression of a Lysosomal Enzyme in Mouse Liver After Sleeping Beauty Transposon-Mediated Gene Delivery: Implications for Non-Viral Gene Therapy of Mucopolysaccharidosis

Background—The Sleeping Beauty (SB) transposon system is a non-viral vector system that can integrate precise sequences into chromosomes. We evaluated the SB transposon system as a tool for gene therapy of mucopolysaccharidosis (MPS) types I and VII…

Risks of Insertional Mutagenesis by DNA Transposons in Cancer Gene Therapy

Recently the Sleeping Beauty (SB) transposon/transposase system has been applied in clinical trials to redirect T-cell specificity through the addition of a transgenic cassette that drives expression of a chimeric antigen receptor (CAR). We have focused on issues relating to insertional mutagenesis in the context of the plasticity of human genomes, the unexpected variability in human genomes elucidated by recent high-throughput, wholegenome sequencing projects of hundreds of individuals and cells therein, and the recently discovered high rates of remobilization of endogenous transposable elements…