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Gene therapy for HIV-1 infection is a promising alternative to lifelong combination antiviral drug treatment. Chemokine receptor 5 (CCR5) is the coreceptor required for R5-tropic HIV-1 infection of human cells. Deletion of CCR5 renders cells resistant to R5-tropic HIV-1 infection, and the potential for cure has been shown through allogeneic stem cell transplantation with naturally occurring homozygous deletion of CCR5 in donor hematopoietic stem/progenitor cells (HSPC). The requirement for HLA-matched HSPC bearing homozygous CCR5 deletions prohibits widespread application of this approach. Thus, a strategy to disrupt CCR5 genomic sequences in HSPC using zinc finger nucleases was developed. Following discussions with regulatory agencies, we conducted IND-enabling preclinical and testing to demonstrate the feasibility and (preclinical) safety of zinc finger nucleases-based CCR5 disruption in HSPC. We report here the clinical-scale manufacturing process necessary to deliver CCR5-specific zinc finger nucleases mRNA to HSPC using electroporation and the preclinical safety data. Our results demonstrate effective biallelic CCR5 disruption in up to 72.9% of modified colony forming units from adult mobilized HSPC with maintenance of hematopoietic potential and . Tumorigenicity studies demonstrated initial product safety; further safety and feasibility studies are ongoing in subjects infected with HIV-1 (NCT02500849@clinicaltrials.gov).

Over the past 15 years we have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC). We propose that the expression of selected RNA-based HIV-1 inhibitors in the CD4+ cells derived from GM-HSPC will protect them from HIV-1 infection and results in a sufficient immune repertoire to control HIV-1 viremia resulting in a functional cure for HIV-1/AIDS. Additionally, it is possible that the subset of protected T cells will also be able to facilitate the immune-based elimination of latently infected cells if they can be activated to express viral antigens. Thus, a single dose of disease resistant GM-HSPC could provide an effective treatment for HIV-1+ patients who require (or desire) an alternative to lifelong antiretroviral chemotherapy. We describe herein the results from several pilot clinical studies in HIV-1 patients and our strategies to develop second generation vectors and clinical strategies for HIV-1+ patients with malignancy who require ablative chemotherapy as part of treatment and others without malignancy. The important issues related to stem cell source, patient selection, conditioning regimen and post-infusion correlative studies become increasingly complex and are discussed herein.

The PML gene of acute promyelocytic leukemia (APL) encodes a cell-growth and tumor suppressor. PML localizes to discrete nuclear bodies (NBs) that are disrupted in APL cells. The Bloom syndrome gene BLM encodes a RecQ DNA helicase, whose absence from the cell results in genomic instability epitomized by high levels of sister-chromatid exchange (SCE) and cancer predisposition. We show here that BLM co-localizes with PML to the NB. In cells from persons with Bloom syndrome the localization of PML is unperturbed, whereas in APL cells carrying the PML-RARalpha oncoprotein, both PML and BLM are delocalized from the NB into microspeckled nuclear regions. Treatment with retinoic acid (RA) induces the relocalization of both proteins to the NB. In primary PML-/- cells, BLM fails to accumulate in the NB. Strikingly, in PML-/- cells the frequency of SCEs is increased relative to PML+/+ cells. These data demonstrate that BLM is a constituent of the NB and that PML is required for its accumulation in these nuclear domains and for the normal function of BLM. Thus, our findings suggest a role for BLM in APL pathogenesis and implicate the PML NB in the maintenance of genomic stability.

HIV-1 Remission after Stem-Cell TransplantationA patient with a 33-year history of HIV-1 infection who underwent stem-cell transplantation for the treatment of acute myelogenous leukemia remained HIV-1 free nearly 5 years later.

Rare cardiovascular diseases, while individually uncommon, collectively affect millions of people worldwide and are associated with significant morbidity, mortality, and economic burden. Despite this considerable impact, most rare cardiovascular diseases lack approved treatments. Developing therapies for rare cardiovascular diseases requires overcoming a unique set of challenges. This includes barriers to accurate patient diagnosis (and therefore to trial cohort generation), small cohort sizes, the choice of effective clinical trial endpoints, unique ethical and regulatory concerns, and the often-substantial costs of such therapies (which may limit public access to treatment). Despite such challenges, the past decade has witnessed a significant increase in the successful development of rare cardiovascular disease therapies. This review provides an overview of the challenges, while also highlighting potential strategies to advance the field.

Apple seeds treated with variable intensity doses of irradiation produce alterations of apple heredity, which are generally characterized by the reduction of tree vigour, change of fructification type, crop capacity, fruit shape, colour and biochemical fruit content. Morphological and productive features of trees derived through mutagenesis and fruit quality were studied on twelve apple genotypes, using 'Jonathan' and 'Golden Delicious' cultivars as control. The analysis of apple genotypes growing potential obtained through mutagenesis showed that there were significant differences in the tree height, trunk diameter, crown diameter and fructification type among the apple trees. Several genotypes ('G-1/7', 'G-1/8', 'G-3/123', 'G-4/131', 'G-9/11') were registered with a high content of total nitrogen and protein in the fruits and 'G-9/11' genotype had the highest content of phosphorus (0.408%). Genotypes 'G-4/101' and 'G-4/131' accumulated a high quantity of nitrates, over the maximum admitted levels of 60 ppm NO3- for fresh fruits. Cu and Zn contents were low, under the maximum admitted limits.

Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest that the alkylating agent cyclophosphamide can enhance immune responses by depleting Tregs. Therefore, we have enrolled a second cohort of patients with advanced melanoma in the clinical trial LUD2002-013 to investigate whether pre-treatment with cyclophosphamide could improve the immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine. The combination treatment led to a significant increase in vaccine-induced NY-ESO-1-specific CD4 + T cell responses compared with the first trial cohort treated with vaccine alone. We could not detect a significant decline in regulatory T cells in peripheral blood of patients 14 days after cyclophosphamide administration, although a decline at an earlier time point cannot be excluded. Our observations support the inclusion of cyclophosphamide in combination trials with vaccines and other immune-modulatory agents.