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Author Topic: Calimmune: Safety Study of a Dual Anti-HIV Gene Transfer Construct to Treat HIV-  (Read 101547 times)

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Offline Hoyland

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Hi dico, sorry to hear that Prof Berkhout has not replied to you. I have no reason to contact him personally and so I really cannot assist any further. Here is his email address, in case you have been using a different one b.berkhout@amc.uva.nl

Offline dico

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I emailed him again :)

Do you know more about the way Prof Berkhout plans to eradicate hiv from the body  ? I know it is a gene therapy aiming to keep the HIV proviral silent inside cells. But I've never seen any scientific paper about this approach. And I am quite dubious about this way as we do not know where the HIV hides... I am sceptical.

Thank you.


Offline dico

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My email to Prof Berkhout :

Hi Prof. Berkhout,

I just wanted to know if you still plan to begin your clinical trial of hiv gene therapy ? I am a French hiv positive man interested by your research.

The American are conducting since last year a gene therapy thanks to Calimmune and Benitech technology. Unfortunately they don't plan to have a trial here in France. What about you ? How can we be more informed about your research ?

Thanks a lot.

Julian

Envoyé à partir de mon smartphone Sony Xperia™



Prof Berkhout answered :

Dear Julian,
Pre-clinical research is moving slowly forward, in part because of limited funding. Thus, we are there yet. Thank you for inquiring.
All the best,
Ben Berkhout


Unfortunately he gave no date for the clinical trial...

Offline dico

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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!"

So JazJon did you hear some good news about the cohort 1?

Offline JazJon

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So JazJon did you hear some good news about the cohort 1?

Nothing yet but I was called back to participate a second time in the Gilead HIV Latency Study​​ again.  (3 hour apheresis)  I'll ask for an update on Calimmune.

Offline dico

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Nothing yet but I was called back to participate a second time in the Gilead HIV Latency Study​​ again.  (3 hour apheresis)  I'll ask for an update on Calimmune.

Thanks.

What is this study ? They take blood from you and that's all ? Fo what purpose ?

Offline JazJon

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Thanks.

What is this study ? They take blood from you and that's all ? Fo what purpose ?

http://www.questclinical.com/#!studies/cjg9
(Scroll down)

Offline dico

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Unfortunately, there were no news of the calimmune trial at CROI 2014.

Anybody here has new information ?

Offline JazJon

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Update.   Looks like I'm on stand by for cohort 3.  Here's a summary of what else I learned.

- San Francisco finally filled the last slot in cohort one and are starting to bring people in for cohort 2 (low dose chemo)

- They are currently 8 months behind schedule because of the unexpectedly high screen fail rate.  One of the reasons, or 'problems', with why it took so long to fill the first cohort is because the FDA did not allow them to screen more than one patient at a time!! Which is at least a 6 week process per patient!

-  They have recently changed the protocol to allow them to screen 4 patients at once, so hopefully that will help expedite cohort 2's screening.

Offline dico

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Great news.

There's a chance you can get ''cured'' with this medium busulfan dose. It would have been better if they'd give you an immunotoxin and a therapeutic vaccine with it but do not forget that it is only a phase I study.

I hope you'll begin this year. I have great hope for the cohort 3 people.

Imagine what a great combination would be this ddRNAi gene therapy coupled with an antibody vaccine (such as the VIP of David Baltimore encoding the PG09/PG16/PG121 antibodies) boosted with a Tcell vaccine (CMV vaccine of Louis Picker) and the dual TLR7 agonist/romidepsin therapy being investigated by Gilead.

Romas Geleziunas of Gilead has made a speach in CROI 2014: they think an activating agent such as an improved romidepsin with a TLR7 agonist taken with intensified ART (Stribild+maraviroc) could lead to a cure. He told the audiance that these drugs could be taken for one to three months, then a prime antibody vaccine boosted with a T cell vaccine could keep the HIV under control for a lifetime.

Offline dico

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I received an email : the first patient of the cohort 2 will begin his theray within 2 weeks.

They have enrolled all of the cohort 2 and people are queueing to be part of the cohort 3.

Offline Seanl

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Is anyone on this forum part of the first cohort for callimune?
Id love to IM you and pick your brains...

Offline dico

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I would also be interested to know how was the whole process? Do you know your VL and CD4?
.thanks

Offline Cosmicdancer

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Do you know how many people are in each cohort?  The link I saw to the clinical trial didn't say.
Summer, 2007 - &$#@?
November, 2007 - Tested poz, 300,000 vl, 560 cd4
Feb, 2008 - 57,000 vl, 520 cd4, started Atripla
2/2008 - 5/2015 - undetectable on Atripla
May, 2015 - UD, switched to Complera
September, 2015 - UD, 980 cd4, switched to Stribild (Complera interacted with acid reflux medication)
January, 2016 - Stribild, UD, 950 cd4
June, 2016 - UD, 929 cd4

Offline dico

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It s a very small trial. Only 4 in each cohort

Offline Hoyland

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Calimmune's collaborator, UCLA, published some new pre-clinical data. UCLA has tracked the long term viability of CCR5 shrna modified HSPCs (blood stem cells) in non-human primates. This is important work as it models the Cal-1 treatment for HIV that Calimmume is currently trialling in patients.

The study showed that about half of the clones contributed to long term (3-10 years)  repopulation. While this is extremely exciting in terms of Cal-1 potential as a long term cure for HIV, it still remains to be seen if sufficient HSPC's can be transfected in the first place in order to provide patients with a viable population to overcome the HIV.

http://www.sciencedirect.com/science/article/pii/S1934590913005614

Dr Chen, a co-author, is on Calimmune's Scientific Advisory Board.

Offline Hoyland

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As mentioned previously, Calimmune is going to expand its clinical trial to Australia. They are now advertising for a Clinical Trial Manager in Australia. In the absence of any official news, this is probably the best indication that the current trial is going well and that the safety profile is meeting expectations.

http://www.seek.com.au/job/26477101

I expect that the company will have to report back to the CIRM soon, as CIRM is funding the current trial. It is unclear how the company will fund the expansion of the trial.

Offline dico

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So is there anybody here who is included in the 2nd cohort ?

Offline Hoyland

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The American Society for Gene and Cell Therapy has released some new publications in readiness for presentation at the annual meeting. The following may be of some interest.

Lentiviral Vector Mediated Gene Therapies Provide Stable Protection Against HIV Infection: The Use of Short-Hairpin RNA to CCR5 and Membrane Anchored C Peptide Entry Inhibitors

From Calimmune

Conclusions:

These results demonstrate the potential for gene-containing lentiviral vectors to treat HIV infection; there is both stability of the insert and absence of negative effects. These results indicate that both of the examined therapeutic genes protect against HIV infection. They show, more importantly, that the combination of these genes in a single construct provides greater protection than either therapeutic alone, indicating an additive effect of the genes. This finding shows great promise for the use of combination gene therapies in the treatment of HIV infection.

http://www.abstracts2view.com/asgct/view.php?nu=ASGCT14L1_702

Optimized Lentiviral Vectors for HIV Gene Therapy: Multiplexed Expression of Small RNAs and Inclusion of MGMTP140K Drug Resistance Gene

From CoH

Gene therapy with hematopoietic stem and progenitor cells (HSPCs) is a promising approach to engineering immunity to HIV and may lead to a functional cure for AIDS. In support of this approach, we created lentiviral vectors that utilized the MCM7 platform to express a diverse set of small anti-viral RNAs and a drug resistance gene (MGMTP140K). Multiple strategies for simultaneous expression of up to five RNA transgenes were tested. The placement and orientation of each transgene and its promoter were important determinants for optimal gene expression. RNA expression from the MCM7 platform with a U1 promoter was sufficient to provide protection from R5 tropic HIV in macrophages and resulted in reduced hematopoietic toxicity compared to constructs expressing RNA from independent Pol III promoters. Surprisingly, the addition of an HIV entry inhibitor and a nucleolar-localizing transcriptional inhibitor (TAR) did not enhance antiviral potency over constructs that targeted only viral RNA transcripts. We also demonstrated selective enrichment of gene modified HSPCs during in vitro expansion in the presence of BCNU. The use of these less toxic, potent anti-HIV vectors expressing a drug selection marker is likely to enhance the in vivo efficacy of our stem cell gene therapy approach to treating HIV/AIDS.

http://www.abstracts2view.com/asgct/view.php?nu=ASGCT14L1_57

http://www.abstracts2view.com/asgct/view.php?nu=ASGCT14L1_680

Offline tryingtostay

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What's the catch?  Does the virus remain in the body and the immune system just not react to it thus leaving people who've been infected with HIV still potentially able to transmit?

Offline buginme2

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What's the catch?  Does the virus remain in the body and the immune system just not react to it thus leaving people who've been infected with HIV still potentially able to transmit?

No.

1. This is a very early clinical trial.  It's not anything yet but they are trying to genetically alter immune cells to make them resistant to hiv.  HIV as with all other viruses cannot reproduce on its own, it needs a cell to do that.  If the cell is immune then HIV can't reproduce in it.  It does not "kill" the virus.

2.  There are NO hiv drugs that "kill" the virus.  They all either 1. prevent hiv from replicating within the Immune cell or 2. Prevent hiv from attaching itself or entering the cell in one way or another.

That's why HIV at this point in time cannot be cured.  All we can do is prevent it from replicating.   
Don't be fancy, just get dancey

Offline Hoyland

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Quote
No.

1. This is a very early clinical trial.  It's not anything yet but they are trying to genetically alter immune cells to make them resistant to hiv.  HIV as with all other viruses cannot reproduce on its own, it needs a cell to do that.  If the cell is immune then HIV can't reproduce in it.  It does not "kill" the virus.

2.  There are NO hiv drugs that "kill" the virus.  They all either 1. prevent hiv from replicating within the Immune cell or 2. Prevent hiv from attaching itself or entering the cell in one way or another.

That's why HIV at this point in time cannot be cured.  All we can do is prevent it from replicating.   

This is true, however, through these genetic modes of action HIV can be turned into a benign virus. In other words, the virus may still exist but it won't have any effect on treated humans. The trick will be to turn this work into a vaccine so that a greater population is exposed to it. The current mode of genetic treatment delivery will not lend itself to this and so a lot more work needs to be done in this area. However, the potential with these gene therapy treatments is that an infected patient may only need one treatment (no meds) to achieve a functional cure, after which, that patient will no longer be susceptible to HIV infection. 

This may not "kill" the virus but it does represent a considerable step forward in the treatment of the disease.


Offline tryingtostay

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This will be an amazing accomplishment if this works.  I am excited and these types of researches give me hope. 

So if this works it will be like a Chicken Pox vaccine, or functional cure, correct? Basically you are immune to it but you may still have it in your system, correct?

What in your opinion do you think is the best approach towards either a vaccine, functional cure, or treatment?  I am routing for the "Kick & Kill" approach of Romidepson from Bionor.  I seems the least complicated and least hazardous.  The little bit I understand about Calimmune is that it's similar to the Berlin Paitent's treatment ???  please correct me here again if I am wrong. 


Offline buginme2

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So if this works it will be like a Chicken Pox vaccine, or functional cure, correct? Basically you are immune to it but you may still have it in your system, correct?

What in your opinion do you think is the best approach towards either a vaccine, functional cure, or treatment?  I am routing for the "Kick & Kill" approach of Romidepson from Bionor.  I seems the least complicated and least hazardous.  The little bit I understand about Calimmune is that it's similar to the Berlin Paitent's treatment ???  please correct me here again if I am wrong.

No.  Not really.  This approach they withdraw your blood.  They alter your own immune cells then inject them back into your body.  The hope is they will reproduce and you will have a group of immune cells resistant to hiv.  hiv will kill all the other immune cells in your body leaving the resistant ones. 

Its not a vaccine. 

This research is very very early in development.  Its still at the basic research phase.  Even if this work its still 10-20 years from the clinic.  And that is a BIG IF.


I dont really have a favorite research area.  In my opinion many of the "cure" research ideas are not very appealing.  They all involve either gene therapy, radiation, stem cell transplants, or high doses of cancer drugs.  None of which I would be jumping for joy over.
Don't be fancy, just get dancey

Offline Hoyland

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Calimmune's mode of action is to modify the blood stem cells which turn into the immune system's T Cells. These cells (in theory) will continually divide and thus extend and increase the resistance to HIV. Here is a description straight from Calimmune's website:


Quote
Dr. David Baltimore, Nobel Laureate and now President Emeritus of the California Institute of Technology, suggested in a Nature journal article over a decade ago, that gene therapy could provide a possible treatment for HIV/AIDS if the genes that block HIV production could be transferred into blood stem cells (precursors to T cells).  HIV-resistant T cells could then be produced by these individuals to maintain the immune/blood system, allowing the body to fight off infections and cancers, increasing one's quality of life, reducing the need for antiretrovirals and thereby eliminating the mortality associated with HIV/AIDS.

Since then, Dr. Baltimore, and his esteemed colleagues have pioneered a blood stem cell therapy that blocks the expression of CCR5, used by HIV to enter T cells.

Because of the rapid ability of HIV to develop resistance to monotherapy, the Calimmune team has included additional proprietary technologies to prevent HIV entry.

The treatment is aimed at controlling and preventing HIV from progressing to AIDS.  Armed with proof-of-concept, and safety/efficacy data, Calimmune continues to enhance the technology and is now in conversations with the FDA to take the first generation therapy of this innovative approach to the clinic.

If successful, the one-time treatment can not only help HIV infected individuals, but it would also be a benefit to uninfected people.  With reductions in viremia in infected individuals, this translates into a reduction in the community burden of HIV infection and that, in turn, has the ability to reduce the overall rate of new infections worldwide.

CoH have looked at this approach but it would seem that they favour disrupting the viral RNA as the virus tries to replicate, thus rendering it impotent.

Both treatments are designed to provide a lifetime of immunity to those treated. However, until the method of harvesting and treating blood cells is made simpler, only health centres that have apheresis facilities will be able to treat patients.

If either of the two trials currently in Pl clinical trials (Calimmune and CoH) proves to be safe and efficacious, I believe that those involved will seek Breakthrough Therapy status from the FDA. This would fast track the treatment in to the general clinical setting but it will do little to solve the problem in 3rd world countries.

Offline tryingtostay

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How fast does this therapy take to become effective?  One hooks up to an apheresis machine and in a day the "transfusion" is complete?  What other methods are they seeing to make this simpler?

Offline Hoyland

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Quote
How fast does this therapy take to become effective?  One hooks up to an apheresis machine and in a day the "transfusion" is complete?  What other methods are they seeing to make this simpler?

How fast? This is one of the questions the current trial is trying to determine and so we will have to wait for results from the trial before the answer to this question is known.

Here is a video made by one of the first Calimmune patients.

http://www.youtube.com/watch?feature=player_embedded&v=ymRJLICsMbQ

As to what else Calimmune is doing, this is a commercial matter and Calimmune is keeping this very much to itself.


Offline tryingtostay

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I'm sorry, I meant when a person sits down with this machine how long does it take to cycle in the new blood stem cells, but it's cool I was just curious.  It would seem like a long process and as mentioned it's not a simple thing to do. 

Offline Matts

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I didnt know how advanced Benitec's ddRNAi is; I think that one should take it seriously :) The TT-034 'one-shot-HCV-cure' trial  starts now and could be approved by FDA already in 2016 as 'breakthrough therapy'; if the trial is successful. I think that a Major Company could make an offer for Benitec or CalImmune within the next years.

http://online.wsj.com/article/PR-CO-20140529-906886.html
http://www.tacerebio.com/tt-034.htm
« Last Edit: June 04, 2014, 03:12:35 am by Matts »
Dovato

Offline tryingtostay

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This is sorta relative to the topic.

If the gene therapy for CCR5 & C46 work against the process of HIV-1 infecting immune cells which leaves the rest of the immune fighting cells to be killed off doesn't this still leave out a few loose ends?  For example isn't the inflammation un-addressed while the non modified immune cells are being killed off?  And for those people who this will work for what does this mean for non progressors who's immune cells are not or slowly effected which can be bad and good???
« Last Edit: June 04, 2014, 11:07:17 am by tryingtostay »

Offline Matts

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I think that we have 2 or 3 AidsMeds guinea pigs for Cal-1, just wait what they tell to all of us in 2015 or 2016 :)

The last presentation of CalImmune tells literally nothing new, not worth to post it. I think that it is a big field experiment and we have to wait.
Dovato

Offline dico

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When Will the the cohort 3 (high busulfan) begin treatment?

Offline dico

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Offline Hoyland

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Dico, those readers who are participating in this trial may know the answer to your question but they are probably subject to a non-disclosure agreement, which prevents them from answering or reporting on the progress of the trial.

Offline Hoyland

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Mathematical analysis and computer simulation supports Calimmune's approach to treating HIV. This modelling suggests that even a 20% modified cell transfection rate of  could be a therapeutic.

Quote
In conclusion we have demonstrated that gene therapy employing entry/fusion inhibitors can achieve substantial clinical impact in terms of long-term preservation of total CD4+T cells counts and forestalment of AIDS. Importantly, this was observed even if only a subset of total cells received the gene construct, indicating that full immune system ablation is not necessary (prior to delivery of the gene therapy) in order to achieve substantial clinical impact. We determined that therapy delivery to CD34+ HSC generally resulted in better outcomes than therapy delivery to CD4+T cells. Maximal impact in our modelling was observed if the uninfected G+ CD4+T cells, in addition to having reduced likelihood of productive infection, exhibited lower levels of bystander apoptosis over G- CD4+T cells. Under this scenario therapy delivery to either CD4+T cells or to CD34+ HSC resulted in substantial preservation of total CD4+T cell counts. The present mathematical modelling demonstrates that gene therapy employing entry/fusion inhibitors represents a promising and potent anti-HIV modality, and that further clinical investigation of these gene therapeutics is more than justified.

http://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1003681?utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+ploscompbiol%2FNewArticles+(PLOS+Computational+Biology+-+New+Articles)

 

Offline dico

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Thanks for sharing Hoyland.

Hope they will combine that with a vaccine as gene therapy alone is not enough.

Offline Hoyland

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Offline tryingtostay

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That's great to hear and I'm hopeful it will stop the progression of the HIV virus into AIDS.  I wonder what it could do for controllers?  Could it possibly give the immune system a break?  Hmm, wonders

Offline dico

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Hi all,

What about the third group with high busulfan dose ?

Did they    begin the treatment ? I know the JonJaz wanted to take part in the third group, did you begin the treatment or not yet ?

Thanks

Offline Matts

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The Charite Hospital Berlin has published a roadmap for a functional HIV cure using
 autologous hematopoietic stem cell (HSC). If somebody has full Access for the Agenda I would be thankful. Do they talk about 10, 20 or 30 years ? :)

http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(14)00137-3

"A roadmap toward clinical translation of genetically-modified stem cells for treatment of HIV


Highlights


•We established a collaborative project between academia and regulatory agencies.
•This roadmap aims to facilitate the process of providing access to a cure for HIV.
•We identified steps and challenges for clinical translation of gene therapy.



During the past decade, successful gene therapies for immunodeficiencies were finally brought to the clinic. This was accomplished through new gene therapy vectors and improved procedures for genetic modification of autologous hematopoietic stem cells. For HIV, autologous hematopoietic stem cell (HSC) gene therapy with ‘anti-HIV genes’ promises a functional cure for the disease. However, to develop such a therapy and translate it into a clinical application is rather challenging. The risks and benefits of such a therapy have to be understood, and regulatory hurdles need to be overcome. In this joint paper by academic researchers and regulators, we are, therefore, outlining a high level roadmap for the early stage development of HSC gene therapy as a potential functional cure for HIV."
----------------------------------
The offical press release of the Charite is only available in german so far. I think a translation will follow:

http://www.charite.de/charite/presse/pressemitteilungen/artikel/detail/schritt_fuer_schritt_zu_einer_gentherapie_bei_hiv/

Dr. Hütter cured Mr. Brown in the Charite; now working for CalImmune. I think that they all are in connection and work in an international network for a possible solution the future.


« Last Edit: November 19, 2014, 02:29:03 pm by Matts »
Dovato

Offline Jmarksto

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Matts;  Thanks for posting this -- it is very interesting.  In terms of 10,20, or 30 years, this excerpt is somewhat telling:

"In this joint paper by academic researchers and regulators, we are, therefore, outlining a high level roadmap for the early stage development of HSC gene therapy as a potential functional cure for HIV."


The fact that this is a combination of researchers and regulators -- and the private sector is not included, with the use of the terms "high level road map" and "early stage development" all indicate more than 10 years.  Just looking at the speed of science I would guess less than 30 years -- so that puts us at 20 years.  That said, who would have thought we would be where we are today with gene therapy and stem cell research ten years ago.
03/15/12 Negative
06/15/12 Positive
07/11/12 CD4 790          VL 4,000
08/06/12 CD4 816/38%   VL 49,300
08/20/12 Started Complera
11/06/12 CD4   819/41% VL 38
02/11/13 CD4   935/41% VL UD
06/06/13 CD4   816/41% VL UD
10/28/13 CD4 1131/45% VL 25
02/25/14 CD4   792/37% VL UD
07/09/14 CD4 1004/39% VL UD
11/03/14 CD4   711/34% VL UD
03/13/15 CD4   833/36% VL UD
04/??/15 Truvada & Tivicay
06/01/15 CD4 1100/50% VL UD
10/16/15 CD4   826/43% VL UD
??/??/2017 Descov & Tivicay
2017 VL UD, CD4 stable around 850
2018 VL UD, CD4 stable around 850

Offline buginme2

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I'd say more like 30 years but thats just a personal opinion.

If your interested in autologous hematopoietic stem cell transplants the fred hutchinson cancer research institute in the united states is currently conducting clinical trials.  Currently they are limiting participation only to those who are hiv+ AND have a blood cancer such as lymphoma or leukemia.

This will never move to the general public ie hiv+ without cancer, unless these trials show specific benefit errr cure in the cancer cohort.

So, at least 30 years.


http://defeathiv.org/clinical-studies/eligibility/
Don't be fancy, just get dancey

Offline Matts

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thx for the link. It seems to be quite difficult with all the chemo and radiation.

The Charite answered my email, but it was the same I can read in the newspapers here: ' they work at full speed on the thing and the first Patient will be treated in 2016; taking haemocytoblasts, altering them with synthetic Anti-HIV genes and injecting them back or something like that.
Allegedly the science is not the problem, more the bureaucratic hurdles.

Ok we will see in 2017 or later :)

http://www.b-crt.de/presse/pressemitteilungen/single-news/?tx_ttnews%5Btt_news%5D=154&cHash=5855cdc7dc15866dbd7126949e6892af&L=1

 
Dovato

Offline Hoyland

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Geoff Symonds is providing an update on the Calimmune project in Miami on Dec 10.

http://www.informedhorizons.com/hivdart2014/pdfs/PreliminaryProgram_HIVDART2014.pdf

Offline Matts

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G. Symond's abstract is online: (page 4)

http://www.informedhorizons.com/hivdart2014/pdfs/EBook_HIVDART2014_FinalV2.pdf

Quote
Background
While ART has the ability to reduce viral load and maintain CD4 count thereby reducing morbidity and mortality, it must be taken daily lifelong, leading to cumulative side effects and resistance can develop due to compliance issues . Cell-delivered HIV gene therapy involves the introduction of anti-HIV-1 genes into blood cells to provide a population of protected cells . Transplantation of CCR5-/- hematopoietic stem cells has recently proven effective as a clinical approach for treatment of HIV-1 infection and cell-delivered gene therapy may inhibit HIV-1 replication and maintain CD4 counts . It has the potential to reduce the reservoir and eliminate or reduce the need for ART .

Methods
We have produced a self-inactivating lentiviral vector (LVsh5/C46) that contains i) a short hairpin RNA directed to the CCR5 HIV co-receptor under the control of the H1 promoter and ii) a C46 fusion inhibitor under the control of the Ubiquitin C promoter . This vector has been used to transduce hematopoietic cell lines and primary hematopoietic cells . The cells have then been tested for viability, phenotype and ability to inhibit replication of HIV-1 . In addition we have conducted studies in the humanized bone marrow, liver, thymus (BLT) mouse in which a control group received non-modified human CD34+ hematopoietic stem/progenitor cells (HSPC), while the treatment group was transplanted with HSPC transduced with LVsh5/C46 .

Results
This dual therapeutic vector showed robust expression in blood cells and strong and sustained inhibition of HIV-1 replication against both R5 and X4 strains of HIV-1 in all cell types tested . In the mouse experiments, splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 . For the LVsh5/C46 treated group, there was no impact on engraftment or multi-lineage differentiation compared the control group and when challenged in vivo with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks post-infection . LVsh5/C46 gene-marking and transgene expression was confirmed stable at 26 weeks post-transplantation

Conclusions
This pre-clinical data strongly support the use of LVsh5/C46 lentiviral vector in cell-delivered gene therapy for HIV and has paved the way forward to clinical testing.

good to know that it works against CCCR5 and CXCR4.

If somebody finds another interesting abstract in the PDF, please post it :)

« Last Edit: January 11, 2015, 02:41:57 pm by Matts »
Dovato

Offline Hoyland

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Unfortunately this material is very old and one has to wonder why the company is resorting to presenting pre-clinical data at a time when it already knows the results of the first cohort of patients in its human trial. What is it that the company is being so coy about?


Offline Hoyland

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The Kirby Institute in Australia has collaborated with Calimmune. Their latest paper deals with an approach to HIV latency.

http://www.nature.com/mtna/journal/v4/n1/full/mtna201467a.html

On the work with Calimmune:

Quote
We have recently demonstrated the TGS activity of our Prom A construct in an in vivo study using the (NOD)/SCID/Janus kinase 3 (NOJ) knockout humanized mouse model (Figure 2),120 where we employed a lentiviral vector to deliver the short hairpin (sh) form of PromA. After the shRNA expression unit is transcribed from the U6 promoter by RNA polymerase III, which terminates at a poly(T) motif coded within the expression unit, both sense and antisense strands are hybridized with a loop sequence linking both strands. The loop sequence is then processed by cellular ribonucleases to form mature/processed double-stranded siRNA-PromA.129 We demonstrated the potential of this approach by reconstituting mice with human PBMC transduced with the lentiviral shPromA construct. This mimics a CD4+ T-cell delivery approach. Upon challenge with HIV-1JRFL, mice reconstituted with untransduced PBMCs had an acute, progressive HIV-1 infection with high viral loads, massive CD4+ T-cell depletion and profound immunodeficiency that occurred within 2 weeks.130,131 Despite this acute, rapidly progressive and aggressive infection, pVL in the mice transplanted with PBMC expressing shPromA was significantly lower than in mice treated with the control mutated shPromA-M2 construct, which does not efficiently suppress the virus in vitro. Mononuclear cells were recovered at sacrifice (day 14 after HIV-1 infection) from the peritoneal cavity and spleen, and CD4+ T cells were markedly reduced relative to CD8+ T in the control mice, while the ratio was relatively preserved in mice transplanted with shPromA-transduced cells. Experiments using mice reconstituted with transduced human CD34 cells are currently underway. The aim is to provide sufficient data using this model system to warrant therapeutic development of these constructs. Our proposed therapeutic strategy would be to use these constructs to enforce latency in patients who have been pretreated with cART and have a residual latent viral reservoir. This strategy offers an alternative approach as a “functional cure,” which is the antithesis of a viral activation or “kick and kill” approach. We hypothesize that this new approach could be used in order to induce and maintain HIV-1 latency, enforcing transcriptionally inactive virus even in patients ceasing cART.

And in conclusion to this paper:

Quote
In the future, ncRNA-based approaches may lead to novel therapies that either enforce HIV-1 latent infection or induce activation of HIV from latently infected cells, allowing control of the reservoir in the absence of traditional antiretroviral drugs.


Offline Hoyland

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More pre-clinical work by Calimmune's partner, UCLA, confirms the CCR5 blocking strategy using HSPC's should work.

http://www.nature.com/mtna/journal/v4/n2/full/mtna20153a.html

Quote
In this study, we characterized selective protection of sh1005-mediated CCR5 downregulated CD4+ T lymphocytes in vivo in HIV-1–challenged hu BLT mice. Our results showed that CD4/CD8 ratios in sh1005-gene modified populations were stably maintained in peripheral blood and lymphoid tissues in CCR5 (R5) tropic HIV-1–challenged BLT mice. sh1005-modified memory CD4+ T cells were also well maintained in lymphoid tissues, suggesting that sh1005-mediated CCR5 downregulation can protect memory CD4+ T cells, the primary target of R5-tropic HIV-1. The frequencies of HIV-1 infected cells were significantly reduced in the sh1005-modified splenocytes, measured by viral reactivation by ex vivo cell stimulation. These results demonstrated that sh1005 is a potent early-step anti-HIV reagent that provides HIV-1 resistance to CD4+ T lymphocytes by stable CCR5 downregulation and can be effective in HSPC gene therapy strategies for HIV-1 disease.

As the strategy is now being tested in the clinic, I am left wondering about the value of this additional pre-clinical work. It cannot be long before the final cohort in the Calimmune trial is dosed and the early results for patients in cohorts 1&2 should be known and I would have thought that those results would be more revealing than additional work in mice.

 


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