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Calimmune: Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-

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JazJon:

--- Quote from: Hoyland on October 09, 2013, 10:44:57 PM ---The latest information released by the CIRM says that the Calimmune HIV trail has produced NO reports of serious safety events and that company is now planning the next trial of Cal-1 which will be conducted outside of the USA.


http://www.cirm.ca.gov/sites/default/files/files/agenda/131009_Agenda_10_Translational_Portfolio_Update_ICOC_1013_final.rev__0.pdf

--- End quote ---

Interesting :)

I asked about this and got a response.

"Hi Jon,
You know you are my number 1 guy right?! funny you mention CIRM, because they will be here next week! I believe what they are really planning to do is 'planned future ex US trials with same product in a different subgroup of HIV patients'  which means that they are going to look into other groups of patients outside of the US as well. That wont effect your participation in the study at all."

Hoyland:
Did anyone attend the Calimmune and Sangamo presentations at the World Stem Cell Summit yesterday? Being in clinical trials and combining cell and gene technologies seems to give these two programs a high profile.

JazJon:
Latest updated: (delay)

"We are still trying to fill cohort 1. We have a waiting list for all of the other cohorts that include chemo, but its been really hard trying to fill the non-chemo arm. We currently have a few guys lined up to screen for the last spot and hopefully one would qualify. Because of the delay, all of the other cohorts must be pushed back as well. We will not know if any of the three qualifies until the end of December/early Jan. If that is the case, we would not be expecting to start the next cohort, small dose of chemo, until probably Feb/March. You are still in the forefront!"

Hoyland:
This paper is the latest work published with collaboration from Geoff Symonds of Calimmune. This seems to be a different approach to Cal-1 but because its underpinning technology is the same the two could probably be incorporated into a single treatment at some future stage.

------
Despite prolonged and intensive application, combined antiretroviral therapy cannot eradicate human immunodeficiency virus (HIV)-1 because it is harbored as a latent infection, surviving for long periods of time. Alternative approaches are required to overcome the limitations of current therapy. We have been developing a short interfering RNA (siRNA) gene silencing approach. Certain siRNAs targeting promoter regions of genes induce transcriptional gene silencing. We previously reported substantial transcriptional gene silencing of HIV-1 replication by an siRNA targeting the HIV-1 promoter in vitro. In this study, we show that this siRNA, expressed as a short hairpin RNA (shRNA) (shPromA-JRFL) delivered by lentiviral transduction of human peripheral blood mononuclear cells (PBMCs), which are then used to reconstitute NOJ mice, is able to inhibit HIV-1 replication in vivo, whereas a three-base mismatched variant (shPromA-M2) does not. In shPromA-JRFL–treated mice, HIV-1 RNA in serum is significantly reduced, and the ratio of CD4+/CD8+ T cells is significantly elevated. Expression levels of the antisense RNA strand inversely correlates with HIV-1 RNA in serum. The silenced HIV-1 can be reactivated by T-cell activation in ex vivo cultures. HIV-1 suppression is not due to offtarget effects of shPromA-JRFL. These data provide “proof-of principle” that an shRNA targeting the HIV-1 promoter is able to suppress HIV-1 replication in vivo.

.....

Using the CD34+ cell–reconstituted NOJ model, we wish to explore a scenario closer to that which we envisage these constructs will be used in human HIV-1 treatment, primarily on cessation of antiretroviral drugs in controlled chronic infection to determine whether lentivirally delivered shPromA constructs can stabilize the viral reservoir on withdrawal of antiretroviral therapy. If the latent viral reservoir could be maintained as effectively silenced by shPromA treatment, these constructs would represent a substantial step forward on the road toward a functional cure, by providing an alternative to the currently proposed eradication strategies than using various viral transcription activating agents, such as histone deacetylase and demethylases.49,60,61 Rather than activating virus and abolishing infected cells, we propose that constructs such as shPromA could be used to lock HIV-1 into latency maintaining transcriptionally inactive virus even in patients ceasing conventional antiretroviral therapy, thus achieving a prolonged remission or functional cure of HIV-1 infection.

http://www.nature.com/mtna/journal/v2/n12/full/mtna201364a.html

Hoyland:
Co-authored by Calimmune and Gero Hutter this paper explains more about the synergy between Cal-1  and the Berlin Patient.

www.mdpi.com/1999-4915/6/1/54/pdf


--- Quote ---Abstract: Human immunodeficiency virus type 1 (HIV-1) infection of target cells requires CD4 and a co-receptor, predominantly the chemokine receptor CCR5. CCR5-delta32 homozygosity results in a truncated protein providing natural protection against HIV infection—this without detrimental effects to the host—and transplantation of CCR5-delta32 stem cells in a patient with HIV (“Berlin patient”) achieved viral eradication. As a more feasible approach gene-modification strategies are being developed to engineer cellular resistance to HIV using autologous cells. We have developed a dual therapeutic anti-HIV lentiviral vector (LVsh5/C46) that down-regulates CCR5 and inhibits HIV-1 fusion via cell surface expression of the gp41-derived peptide, C46. This construct, effective against multiple strains of both R5- and X4-tropic HIV-1, is being tested in Phase
I/II trials by engineering HIV-resistant hematopoietic cells.
--- End quote ---

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