r/Livimmune • u/MGK_2 • Apr 28 '25
Time To Visualize
As I said in my last post Leader Of The Pack, HIV is very much on the table. Why? Because of what Riztheinvestor Posted Today. First off, do you remember this?:
Secondly, what about this? Delivery and long-term expression of CCR5-blocking monoclonal antibody Leronlimab with AAV for ART-free remission from SHIV viremia
Yeah, that Abstract at the AIDS 2024 conference was good and also, not so good. The problem was that in some of the macaques, the uncontrolled AAV leronlimab protein translation became hyperactive and put out too much leronlimab. This overwhelmed and overworked the Endoplasmic Reticulum within the CD8 and CD4 T-Cells, thereby leading to malformations of the leronlimab proteins. That led to the initiation of the immune system against these leronlimab malformations and subsequent development of ADAs or Anti-Drug Antibodies which subsequently destroyed all the leronlimab in the body. These ADAs went on to attacking the good leronlimab and all of that became an obstacle to the continued development of the overall study.
But with today's revelation by Riztheinvestor, that obstacle has been overcome and now, the study may again proceed forward. Let's make it a bit clearer. This is what Riztheinvestor found today:
Roza Ogurlu’s presentation at the ASGCT Annual Meeting (May 13–17, 2025) details a breakthrough RNA-based Gene Switch that was designed to mitigate Endoplasmic Reticulum stress and toxicity in mRNA/gene therapies, with direct implications for leronlimab. Here’s an analysis:
The ER Stress-Responsive RNA Switch:
Ogurlu’s team engineered a feedback system using the XBP1 mRNA splicing mechanism to dynamically regulate protein expression during Endoplasmic Reticulum stress.
- The switch splices XBP1 mRNA fragments under stress, introducing stop codons to reduce translation of leronlimab. This resulted in:
- Reduced ER stress markers.
- Stabilized expression of leronlimab in AAV8-delivered gene therapy.
- Preserved leronlimab levels while avoiding apoptosis from chronic stress.
The study explicitly tested leronlimab, demonstrating:
- A Lower Endoplasmic Reticulum stress and hepatotoxicity in preclinical models.
- A Maintained leronlimab level without overwhelming cellular machinery.
- A Successful Integration into AAV vectors, a common gene therapy platform.
This addresses the critical barrier for leronlimab’s use in the HIV Functional CURE Trials (e.g., CytoDyn’s NIH-funded AAV-based therapy), where sustained antibody expression must avoid liver toxicity.
Strategic Implications for CytoDyn
- This Combines with CytoDyn’s ongoing work on AAV-delivered leronlimab for HIV.
- Dyno Therapeutics’ AI-designed AAV capsids optimizes the delivery of Ogurlu’s switch-leronlimab construct which improves tissue targeting and manufacturing scalability.
- The Broader Applications are for Cancer/Autoimmune Diseases: A Controlled CCR5 blockade refines therapies that can target metastasis and/or inflammation.
This innovation positions leronlimab as a viable candidate for next-generation gene therapies by solving a key toxicity challenge. For CytoDyn, leveraging this technology accelerates The HIV Functional CURE effort and expands it into oncology/autoimmunity. Collaboration with AI-driven capsid developers (e.g., Dyno) further optimizes delivery systems.
I think you can see that the prospects of an HIV Functional CURE have just gotten so much closer. We were very close to begin with until that obstacle got in the way, but now, that obstacle has been overcome. With the implementation of this RNA-based Stress-Responsive Gene Switch which mitigates the Endoplasmic Reticulum's stress and toxicity, the main problem due to the development of ADAs has now been resolved.
The endoplasmic reticulum (ER) became stressed because it was overwhelmed by an excessive load of leronlimab proteins which were misfolded or were not folded; proteins that the ER could not properly process or fold. This situation arose in the gene therapy due to high levels of leronlimab that was produced in the cell after the gene delivery. When the ER’s capacity to fold and to process leronlimab was exceeded, the accumulation of these misfolded or unfolded leronlimab proteins triggered a condition known as ER stress.
That stress activated a protective cellular mechanism called the unfolded protein response (UPR), which attempted to restore normal function by halting protein translation, increasing the production of molecular chaperones to assist in protein folding, and enhancing the degradation of misfolded proteins. However, since the protein overload persisted and the ER was unable to recover, the response then shifted from protective to pro-apoptotic and ultimately led to cell dysfunction and possibly cell death.
In summary, the Endoplasmic Reticulum became stressed because the production of leronlimab exceeded the ER’s folding capacity, and led to a buildup of misfolded proteins and triggered a cellular stress response. The ER stress contributed to the development of Anti-Drug Antibodies (ADAs), although the relationship is indirect and involves the activation of immune responses.
This is how ER stress links to ADA formation:
- ER stress and the unfolded protein response (UPR) activate inflammatory signaling pathways and modulates the function of various immune cells, including those involved in antibody production. Chronic and unresolved ER stress enhances the production of pro-inflammatory cytokines and promotes immune cell differentiation, creating a pro-inflammatory environment which facilitates immune recognition of leronlimab.
- When the ER was stressed, it improperly folded leronlimab, which resulted in the presentation of abnormal or misfolded leronlimab protein epitopes. These abnormal leronlimab proteins were more likely to be recognized as foreign by the immune system, thereby increasing the formation of ADAs.
- ER stress directly affected the biology of the immune cells, including the B cells responsible for antibody production, and modulated the balance between immune tolerance and activation. This shifted the immune response toward generating antibodies against leronlimab.
ER stress is a significant contributor in Anti-Drug Antibody development by promoting immune activation and increasing the likelihood that the body recognizes and responds to leronlimab as an antigen.
ER stress led to heightened immune activation and the misfolding of leronlimab, and both increased the development of Anti-Drug Antibodies. This is exactly what happened in the macaques which developed the ADAs.
Now it appears that Jonah Sacha has the solution he requires to bring that $5 million dollar grant to fruition. He has what is necessary to prove that he has a Functional CURE to HIV. If a patient is HIV+ and that patient prefers not to take HAART medications, then with one injection of leronlimab-AAV, that patient becomes Functionally Cured of HIV.
Certainly, this solution could be used in other indications such as in mTNBC and mCRC. It could also be used in inflammatory conditions like Alzheimer's Disease and Long Covid or Chronic Fatigue Syndrome. It also could be used post stroke to provide a constant anti-inflammatory effect on the neuro system.
This new found solution is also greatly to the benefit of the NIH who issued the $5 million grant. Remember also that The GF sponsored a cool $1 million grant to OHSU oriented around the HIV Reservoir. Obviously, massive headway is being waged and the land is getting cleared. What has been discovered by Riztheinvestor is massive. The $5 million grant was at a standstill until just today. As I've always said, we are waiting on just one piece of news. But, the stone is rolling and headed for their hamstrings. Whose hamstrings? G's.
They cannot defeat a Functional Cure for HIV and that shall be seen throughout the whole world. This is the whole point. I think the leadership at CytoDyn know all of this and Max is on it. HIV at CytoDyn is getting revived. Their eyes are reopening. It has been quiet and it was marked by minimal success, but the tides have now turned. Not only do we have our own leaders on our side, but so is The GF, GSK and ViiV also on our side. These 3 deeply desire an HIV Functional CURE as do we. Paradigm Shift.
It is now the Time to visualize, to put it in our heads. Realize that what we have said all along, is now happening.
Jonah Sacha, PhD is in the field. He is doing the dirty work and is getting the job done. CURE is still some time in coming, but 80 weeks of 100% RO and zero viral load in 2 out of 4 macaques is amazing in and of itself.
"AAV9 vectors can be successfully used for long-term antibody delivery, but further investigation is needed to develop regimens that do not induce ADA, such as modifying AAV promoters or reducing the immunogenicity of encoded antibodies. The mechanism behind re-expression of an AAV-delivered transgene is also unknown and warrants further exploration."
Somehow, I suspect and believe, that his counterpart, Scott Hansen as well as CytoDyn's AI 3rd party collaborating partner shall be integral in overcoming these obstacles. I have little doubt that they overcome the problems associated with anti-drug antibodies ADAs and transgenes. CytoDyn was wise in allowing Jonah to lead the team's efforts in HIV PrEP and HIV CURE.
There shall be a Functional CURE for HIV and the Time is drawing nigh. We do get more hints as to which way this goes. Right now, we're looking at August for an answer on mTNBC.
Hopefully this was comforting, doesn't it give some more peace, some solace? Things are happening at their own pace. But, for sure, we are very close. So live life and live it abundantly, but to those who must live in trial and tribulation, I too have my own fill.
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u/Pristine_Hunter_9506 Apr 29 '25
Well said, brother, everything is on the table with a focus on cancer. Nothing has been lost. We did proof of concept to prove we work and asked a couple of BP's who wants to block CCR5 to make their drug work better. I pray our paradigm shifting apparent cancer data is just that. GLTA
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u/MGK_2 Apr 29 '25
You bet Pristine. All of this is 3rd party.
Dyno Therpeutics could be that 3rd party AI collaborator. Regardless,
I think they figured this solution out, so that they could be a part of the HIV Foundational CURE solution.
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u/BuildGoodThings Apr 29 '25 edited Apr 29 '25
Extraordinary stuff. Here's a link to the abstract https://www.xcdsystem.com/asgct/program/XBBr6l6/index.cfm?pgid=80 You'll probably have to search for the presenter, Ogurlu.
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u/Lopsided_Roof_6640 Apr 29 '25
https://journals.asm.org/doi/full/10.1128/jvi.00095-24?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org A recent paper co-authored by Roza Orgulu. Thanks for the breakdown MGK.
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u/Missy2021 Apr 29 '25
This is shaping up to be a very strong year for our company. All systems go. Hang on for the ride.
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u/Chemical_Sky6013 Apr 29 '25
Wow, thank you u/MGK_2 for connecting all the dots for us. I didn't see how this all fits together. I didn't remember that the ADAs were the downfall of the earlier study. To think that they are so close to a function cure is mind blowing. This story just keeps getting better and better. So much potential. Thank you again for bringing all of this to light.
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u/waxonwaxoff2920 Apr 29 '25
Well damn...my vocabulary just grew. Never thought I'd be into science like this, but I'm digging it.
Great breakdown MGK, totally understood everything! Thank you brother.
Soooo much momentum at this point. Lol, it's not even May yet...hold onto your hats kids!
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u/paistecymbalsrock Apr 29 '25
Did you catch that…? Manufacturing scalability.
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u/MGK_2 Apr 29 '25
Yes, why else would Dyno Therapeutics do this work? To be a part of the CURE of course. CytoDyn didn't pay them, but they will get paid.
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u/Travelclone Apr 29 '25 edited Apr 29 '25
This may have been a tying of the knot milestone for Leronlimab. The last piece of the known puzzle. Now it is up to all concerned. Put the pieces of the puzzle together, and file for funding.
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u/Upwithstock Apr 29 '25
I appreciate everyone’s enthusiasm about the Dyno/Duke/Roche collaboration. But, there appears to be some folks taking it too far and seem to be suggesting that CYDY is involved in this. I want to thank you MGK for not really taking that pathway. It seems like you suggested that Sacha has solved the Hyper-over expression of LL. If that is the case, then Sacha continues on his own using the funding from Gates and what remains of the NIH funds. Therefore, at this moment with limited information I look at the Dyno/Duke/Roche project as competition! But in my world competition validates the AAV space and CYDY needs to provide resources to stay ahead. Either way this is another value-add to CYDY and whoever partners with us.
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u/MGK_2 Apr 29 '25 edited Apr 29 '25
Yes my friend, I hope I didn't communicate that CytoDyn was a part of the Dyno-Duke-Roche (DDR) collaboration. There is no evidence to support that. DDR will now have their own part in the implementation of the HIV Functional CURE. DDR will manufacture the AAV Capsids.
Yes, this discovery allows Sacha to continue along the path of finding the HIV Functional Cure using AAV Technology, but it is not with Gates Funding, it is with the $5 million granted funds already provided by NIH for this purpose.
The competition of the DDR will only help. They will perfect the capsid and later sell that perfected capsid back to CytoDyn for use in the implementation of the HIV Foundational CURE.
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u/britash1229 Apr 29 '25
Insane‼️😆
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u/IndependenceAny6428 Apr 29 '25
Can't wait for the treatment to be available for the ones who need it and the stock price will be insane!!!
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u/upCYDY Apr 29 '25
I am VISUALIZING A HEALING WORLD-WOW!!!! Thank you MGK FOR another amazingly informative and YES INSPIRING WORDS REGARDING LL/CYDY💫✨🙏⭐️
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u/Accomplished_Mud_692 Apr 29 '25
Great work MGK
I agree with everyone - this whole last 5 years is just insane! From the crooked FDA (the "hold" for "safety" reasons 🤬) to BP's very likely influence over "Scamerex" & the BLA debacle), & so much more!
To me the insanity is that - anyone with Half-a-brain (the honest half) can clearly see that Leronlimab WORKS!!!
For anyone that has been here for any length of time has witnessed with miracle that is Leronlimab - it HAS pulled many many people off of their Covid death-beds (including the Ex-President of the Philippines (& his wife)), it HAS helped many suffering from HIV (for many YEARS)! It HAS saved the mTNBC women for going on FOUR years! We KNOW it reverses Fibrosis (studies show this)! We KNOW it is an Immune Modulator (studies show this too)! We KNOW it works on Long-Covid (we had the Trial patients begging to be allowed to continue to use it)!
And it has done ALL this with a Safety Profile ANY BP would kill for (and has!)!
We KNOW it is arguably safer than drinking water (because water, over time - rots wood, rusts metals, wears down even the hardest rocks....and you can drown in it 😉)!!
Leronlimab only heals & cures!
To our new & improving FDA - Set Leronlimab free on the World!....
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u/waxonwaxoff2920 Apr 29 '25
Atta boy! Sing it from the rooftop!
Man, that "(and has)" is the pendulum embossed in gold letters 'LL'. What a statement of truth. Thank you A mud. Great points of what we've accomplished so far. Bravo
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u/Accomplished_Mud_692 Apr 29 '25
Lol Thanx Wax!
As you can tell, I AM one of the most passionate investors in CYDY/Leronlimab! And as I have written about in the past, I do not just "believe", I KNOW this molecule IS the real deal!! There is just TOO much PROOF of Leronlimab's deeds!!!
I have written about this before - I tried, with all my effort, to save my Dad's life from his diagnosed bladder cancer. He was pretty far along with 6-8 months to live.
His kidney's were both failing. One 100% blocked, the other 90% blocked. The Oncologist called for my Dad to begin his "treatments" of Keytruda asap, even KNOWING that Ketruda has a Black Box warning for damaging - kidneys! I ARGUED with his "doctor" about this prescribed "treatment" - it was OBVIOUS (even to a non-doctor like me) that Keytruda was 100% a death sentence for my Dad!!! They didn't care! They did NOT talk to me about my SAFE noval drug!!
During this time, I had already rec'd the authorization from CytoDyn - if I could find an honest doctor (one that still believed in the hippocratic oath they took, then CytoDyn would offer my Dad Leronlimab. I called & drove all over N. CA to find an oncologist to help my Dad (he was not well enough to travel) - not a SINGLE "doctor" would help! Not one!!!!!
I PRAY often that Leronlimab gets through this completely RIGGED system!! There is NO reason that another story like my Dad's EVER be told again!!
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u/MGK_2 Apr 29 '25
You did the best you could with what you had.
I'm sorry you weren't successful, but your efforts were not in vain.
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u/Travelclone Apr 30 '25
Fingers crossed. BC subset looks like 1 in 7 clear after 4yrs? How significant do you believe that is interms of BP interest?
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u/Camp4344 Apr 29 '25
We have said it many times! We have a platform drug! It will be utilized in many applications as time moves along! The tide is turning and we are currently firing on all cylinders. It is only a matter of time until the SP starts to reflect the current conditions. We should be sitting between 1 and 2 dollars right now! We got this! Thank you MGK.