Only problem with AAV transgene product (leronlima

Only problem with AAV transgene product (leronlimab) production waning is that you can't re-dose with AAV, as the body builds up immunity to it after the first dose.

Now if one could encapsulate leronlimab mRNA in LNP, that could be redosed. Also, one can re-dose with naked DNA and electroporation in vivo, with one company investigating so-called long term antibody production as dMAb (DNA based monoclonal antibodies). I know the military is *very* interested in this technology as a rapid pathogen countermeasure.

I don't think anyone has tried gene therapy for monoclonal antibody production in humans just yet, but I think Moderna might have done phase 1 for antibody against chikungunya, which they killed afterwards.

If one is going to do gene therapy to produce antibodies, it would be good if it could be re-dosed. If it is to be used against HIV, why not just make HIV broadly neutralizing antibodies too, to go with leronlimab? I hope it works out so that all that is needed is leronlimab to turn off CCR5 for a while. It looks like it will be a functional cure (drops HIV below detectable levels), but unclear if it will be a sterilizing cure (removes all HIV from the body so don't need any therapy again).

I forgot that Sacha has the NIH R01 grants to study all this, and will be using AAV to infect B and T cells, which aren't usually long lived cells. In terms of turning "off" leronlimab production, I suppose one could just wipe out all the transfected B and/or T-cells, at some cost to the immune system.

https://reporter.nih.gov/search/MqjH24xtlU-kk...s/10371617

Quote:

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Evolving Novel AAV Vectors for Gene Therapy to Cure HIV
Project Number1R01AI166969-01

PROJECT SUMMARY With the most people ever in history currently living with HIV, stopping the HIV epidemic remains imperative. Combination antiretroviral therapy (ART) limits viral replication, but is not curative. Thus, there is an urgent need to design a functional cure via elimination of the viral reservoir. Timothy Brown, aka the Berlin Patient, and Adam Castillejo, aka the London patient, were cured of HIV following leukemia-related, MHC-matched, allogeneic hematopoietic stem cell transplantation (HSCT) from a CCR5-deficient donor. While a CCR5-deficient immune system can demonstrably yield a functional HIV cure, allogeneic stem cell transplantation is not scalable to the general population and alternate approaches are needed. We have demonstrated that the CCR5-specific antibody Leronlimab can pharmacologically mimic a CCR5 deficient donor by occupying all available CCR5 molecules. In order to deliver Leronlimab as a gene therapy option, new delivery modalities are needed. Here, we are proposing to utilize our novel directed evolution technique to generate AAV vectors specific for T and B cells. These novel AAV vectors will facilitate in vivo delivery of Leronlimab expression here, but more importantly will support the future use of other anti-HIV approaches including CRISPR-Cas9, chimeric antigen receptors, and broadly neutralizing antibodies by delivering these therapeutics to the relevant immune cell type. In specific aim 1, we will generate and characterize AAV bearing capsids that target T and B cells specifically across both macaques and humans. In aim 2, we will demonstrate proof-of-concept utility of these new AAVs by delivering Leronlimab to SHIV-infected, ART suppressed macaques to determine if a functional cure can be achieved with this approach. This work would expand our knowledge of the mechanism of HIV cure by showing the utility of long-term antibody-based competitive CCR5 inhibition and establish a new set of AAV vectors to support in vivo delivery of anti-HIV therapeutics.

PROJECT NARRATIVE The development of curative approaches for HIV infection is now recognized as both a necessary and attainable goal. Hematopoietic stem cell transplantation resulting in a CCR5-deficient immune system has been shown to functionally cure HIV infection in two separate patients, but such an approach is not scalable to the general population. We propose here to develop novel AAV vectors targeted to immune system cells to support delivery of therapeutics such as HIV-targeted CRISPR-Cas9, chimeric antigen receptors, broadly neutralizing antibodies, or CCR5-blocking antibodies to mimic a CCR5-deficient immune system.

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Exciting to hear about that first monkey, though!