[STUDI] Sangamo: CD4 e staminali resi CCR5- mediante ZFN II

[Dora]

Questa è la continuazione del thread [STUDI] Sangamo: CD4 e staminali resi CCR5- mediante ZFN, che può essere trovato a questo indirizzo: http://hivforum.0sites.net/Lilanew/viewtopic.php?t=3952




ICAAC 17-20 settembre 2011 (http://www.icaac.org/ - qui anche il programma e i link agli abstract) - Sangamo presenterà due lavori sull’SB-728-T. Si tratta dei risultati di due sperimentazioni che stiamo seguendo da mesi (anzi, anni) e non vedo l’ora che sia metà settembre.

Sabato 17, nella sessione New Therapies for HIV and HCV Ron Mitsuiasu parlerà di Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-Cells to Aviremic HIV-Infected Subjects with Suboptimal CD4 Counts: i dati completi della fase 1 di somministrazione di CD4 modificati a pazienti HIV+ aviremici.

Background: La ricostituzione immunitaria rimane un problema per quei pazienti HIV+ aviremici che, nonostante la HAART, hanno un basso numero di CD4. Abbiamo già in precedenza reso pubblici i dati preliminari del trasferimento dell’SB-728-T in pazienti HIV+ aviremici. Riportiamo ora l’arruolamento completo dei pazienti per questo studio di fase 1 e i dati relativi a sicurezza, aumenti nei CD4, persistenza dell’SB-728-T e sua collocazione nella mucosa gastrointestinale.

Metodi: 9 persone HIV+ aviremiche con CD4 fra 200 e 500 cellule/ mm3 sono state arruolate in 3 coorti, che hanno ricevuto rispettivamente 10, 20, e 30 miliardi di cellule. L’SB-728-T ha portato a una modificazione del CCR5 del 25+6%. Dopo reinfusione, i pazienti sono stati monitorati settimanalmente per 1 mese, poi mensilmente per 11 mesi.

Risultati: la durata media del follo-up per tutti i soggetti è stata di 218 giorni (22-366). I dati (media + deviazione standard) fino al giorno 28° sono disponibili per i primi 8 soggetti. L’infusione di SB-728-T è stata ben tollerata, con eventi avversi di leggera entità e reversibili correlati all’infusione. Le conte dei CD4 nel sangue periferico sono aumentate di 216+192 cellule/ mm3 al giorno 28° (range: da 19 a 617), con il ristabilirsi di un rapporto CD4/CD8 normale in 4 dei 7 soggetti che avevano rapporti non normali al basale. L’SB-728-T misurato con la nested PCR [PCR con primer annidati] ha raggiunto il 28° giorno un range da 0.2 a 2.8% di CD4 nel sangue periferico ed è persistita per tutta la durata del follow up. L’SB-728-T è stato individuato nella mucosa rettale di 6 pazienti già al 14° giorno ed è arrivato a costituire oltre il 6% dei CD4 della mucosa al giorno 90°.al CD4 cells at D90.

Conclusioni: l’infusione di SB-728-T nei pazienti HIV+ è stata ben tollerata. Si sono visti aumenti consistenti nel numero dei CD4 in tutti i soggetti. L’SB-728-T è stato rilevato con frequenze di 5,5 volte superiori rispetto a quanto previsto, e ciò suggerisce un’espansione di queste cellule. Il livello di marcatura genetica è di circa 1-log maggiore che negli studi in cui si è tentato un transfer adottivo sui CD4 in precedenza. L’SB-728-T si distribuisce normalmente nella mucosa gastrointestinale e aumenta nel tempo. Questi dati preliminari suggeriscono che l’SB-728-T offra la possibilità di ricostituire il sistema immunitario nei pazienti HIV+.


Di questa lezione spero vengano rese disponibili almeno le diapositive.

Domenica 18, invece, nella sessione di poster dedicata alla Antiretroviral Therapy of HIV-1 Infection, Carl June parlerà di HAART Treatment Interruption following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T-cells (SB-728-T) to HIV-infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load.

Il poster di June ancora non è disponibile. Credo verrà pubblicato durante il congresso.



P.S. Molte grazie a Melisanda per la segnalazione.

[Eilan]

Parla Matt Sharp!

Ricostruisce la sua storia clinica, e ora parla del trattamento, dice che non ha avuto nessun effetto collaterale, e che fra sei mesi avrà terminato lo studio. Ha incontrato anche Timothy Brown.

http://www.aidsmap.com/HIV-gene-therapy/page/1793127/

[Dora]

Non c’è che dire: questo Michael Slattery è proprio innamorato!

Al di là dei toni enfatici e quasi elegiaci, nonché del presagio del Nobel a Carl June, mi pare comunque che la sottolineatura della presenza di una relazione targata Sangamo fra i "late breakers" dello ICAAC il 18 settembre prossimo faccia ben sperare in qualche notizia interessante.
Si tratta della seguente relazione, presentata da Carl June, cui avevo accennato all'inizio del mio primo messaggio: HAART Treatment Interruption Following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T- Cells (SB-728-T) to HIV-Infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load, di cui ancora non si conosce nulla più del titolo, sul quale Slattery esercita le sue arti esegetiche nell'articolo qui sotto.


Sangamo's Late Breaking, Game Changing News At ICAAC

September 1, 2011 – Michael Slattery

On September 17-20 the 51st Interscience Conference On Antimicrobial Agents and Chemotherapy meeting will take place in Chicago. Conference attendees have always referred to this meeting by its abbreviation; ICAAC, pronounced “ick-ack." It’s considered to be the premier meeting on infectious diseases and antimicrobial agents and is organized by the American Society for Microbiology.
A brief background that provides some context for Sangamo’s (SGMO) exciting, game changing, human clinical trial presentations at ICAAC:

Many individuals reading this will be unfamiliar with the SCID-Hu mouse.It stands for Severe CombinedImmunoDeficiency – Human / Mouse. These amazing little animals have been transplanted with functioning human immune systems, enabling researchers to conduct “human” clinical studies in an inexpensive and expedited manor. Many of you may remember the “boy in the bubble” who suffered from the same immune deficiency as these mice. Because these mice are born without a functioning immune system, they do not reject the human tissues and cells that get transplanted into them, enabling these mice to becoming the host to a functioning human immune system.



One of Sangamo’s collaborators, Paula Cannon Ph.D., from the USC Keck School of Medicine, recently utilized this model to examine the efficacy of transforming human stem cells (CD34 cells) making them resistant to HIV by deleting their CCR5 receptors. She utilized Sangamo’s Zinc Finger Nucleases (SB-728) to accomplish this. The desired outcome would be HIV resistant immune cells derived or differentiated from these stem cells.



When these mice were infected with HIV an amazing feat was accomplished as the first slide demonstrates. The mice went through what is termed a normal seroconversion process, becoming infected and developing high levels of the HIV virus as measured by a very sensitive assay, polymerase chain reaction (PCR). Here is where any comparison to the normal disease process abruptly ends. The mice that received the transformed CD34’s and their resulting HIV resistant T-cells eliminated all viruses from the mice immune systems as the line chart indicating their viral load below (-ZFN-) clearly demonstrates. The bar chart (second chart) demonstrates how these transformed immune cells traffic to important immune sites demonstrating their normal functioning. Keep in mind you are looking at data from human immune system cells.

Back To ICAAC

Sangamo and its collaborators will present the results of a recent human clinical trial in a Late Breaker on Sept. 19. Late Breakers (for those of you who have not attended one of these scientific meetings) are usually the last public session of the meeting and are reserved for cutting edge, exciting, news-worthy advancements that could not be submitted earlier because the research was still ongoing. Thus "late breaking news." These presentations are highly coveted slots and competition for them is intense. The details of this presentation are also embargoed so no abstract of this presentation is currently posted on the ICAAC web site.But we do have the very revealing title used here with ICAAC’s permission of Sangamo’s Late Breaker presentation:

“HAART Treatment Interruption Following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T- Cells (SB-728-T) to HIV-Infected Subjects Demonstrates Durable Engraftment and Suppression of Viral Load”

So what is Sangamo's exciting breaking news announcement? If we break down this title it becomes clearly evident. “HAART (Highly Active Anti-Retroviral Treatment) Treatment Interruption (interrupt antiviral therapies) Following Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4 T- Cells (SB-728-T) to HIV-Infected Subjects (Remove the HIV+ patients CD4 T-cells, transform them into HIV resistant CCR5 receptor negative cells utilizing Sangamo’s SB-728-T Zinc Finger Nucelase and re-infuse them back into the trial subject) Demonstrates (results) Durable Engraftment (transformed cells survived and moved around the immune system and organs in a normal manor) and(late breaking news here) Suppression of Viral Load.”

These clinical trial participants were removed from their antivirals, their viral load was allowed to rise and the Sangamo altered T-cells were able to suppress viral load. Not just reduce it, but suppress it. Which is exactly what the chart above demonstrates in the SCID-Hu Mouse model.

This is the ultimate test of any therapy attempting to confront HIV. The success demonstrated here is a game changer for the entire pharmaceutical industry. Anyone with drugs in distribution or treatments in development for this affliction has just received a new bar to judge the entire paradigm against.
The Sangamo therapy will be expensive and that price point will only make economic sense if there is a comparable reduction or elimination in the cost of antiviral therapy for those who receive it. This is the first indication that life without toxic and debilitating long term antiviral therapy is possible. It also makes the pricing of Sangamo’s therapy a lot easier to digest for insurance companies and Medicare. This makes Sangamo a much more attractive partner to any large pharmaceutical.This study is a tipping point for everyone with an HIV antiviral franchise.If you want to continue making money in the largest HIV markets then you need to partner with Sangamo. If you are tired of making money in this market than all you need to do is continue developing the next multi-combinations of 3, 4 or 5 antivirals in one pill.

Am I reading too much into this? Unless Sangamo’s collaborators intentionally went way out of their way to mislead the entire scientist community at this meeting and its organizers, then no. Such a folly would severely damage their scientific reputations and make it more difficult to be published and accepted for presentations at similar meetings in the future. It would have a dire and detrimental impact on the chances for any future governmental contracts or grants. It would also ignore the fact that the scientists at Sangamo and their collaborators are incredible, highly respected, world-renowned researchers [speriamo che tu non stia prendendo una cantonata, caro Signor Slattery!].

Just a few weeks ago a storm of media attention surrounded Dr. Carl June who had just announced that his University of Pennsylvania team had successfully cured two patients suffering with CLL or Chronic Lymphoid Leukemia. This was accomplished utilizing cells that had been transformed with an altered form of HIV producing a vector to target these individual cancers. There is an excellent audio interview of how they accomplished that here. These individuals were weeks away from death and are now living normal healthy lives. Dr. June and his team are the first to successfully focus the immune system on a specific disease-causing target, marshaling the immune system to remove it, while setting up those same cells to perform immune surveillance, guaranteeing that the disease does not return. That all but guarantees Dr. June the Nobel Prize for Medicine within the next couple of years. (Video here) This caliber of scientist does not print anything they can’t prove; much less generate misleading titles for their presentations at the most prestigious microbiology meeting of the year.
Dr. June is also the Senior Researcher on this Sangamo study. (*)

What are the implications for Sangamo’s near term share price? Given this amazing result and the other positive results to be released on Sept 17 and 19 at the same meeting, I expect to see the share price ramp up dramatically in the next two weeks with a big spike on Monday Sept 20.They have another positive catalyst in the releases of top-line clinical results from the Phase IIb study in diabetic neuropathy utilizing its VEGF-A treatment, SB-509. That data will be released before the end of this year. That should set this stock on a steady upward trajectory for the remainder of 2011.


Disclosure: I am long SGMO.



(*) Il lavoro di June sulla leucemia è IMPORTANTISSIMO e quando Slattery parla di premio Nobel nel giro di un paio d'anni, anche se pecca di entusiasmo, NON sta parlando a vanvera (come sarebbe pronosticare un Nobel alla Ensoli, per esempio). Noi abbiamo accennato a questo successo della terapia genica in Una 'chiave' genica per battere leucemia.

[Dora]

Che sfinimento questo stillicidio di *anticipazioni*.



Da: blogs.nature.com

(Di questo incontro fra esperti organizzato a Philadelphia da amfAR non riesco a trovare altre tracce, a parte la fine del post citato: Approval of a therapy like Sangamo’s will be years in the making, and the final product may look significantly different from the treatments they are currently testing. Gene therapy, says June, “is held to a higher standard than other treatments.” The amfAR meeting was held in part to discuss strategies for improving this kind of therapy, from using different cell types, to different vectors for modifying genes, to ways of expanding the cell population to be transplanted. The mood was upbeat, despite the many challenges and questions that remain about whether a cure is possible. “We still don’t know the mechanisms of how the Berlin patient worked,” says June. “We now have now a tool set to dissect [them].”)

[Dora]

Adam Feuerstein, opinionista di TheStreet, spiega perché le azioni di Sangamo saranno quelle da tenere maggiormente d'occhio la settimana prossima.
Da aggiungere che, proprio il 21, Edward Lanphier, presidente e CEO di Sangamo, parlerà dell'SB-728-T alla UBS 2011 Global Life Sciences Conference, spiegando agli investitori i risultati presentati all'ICAAC domenica (investor.sangamo.com).

[Eilan]

Per oggi...

[thelondonsuede]

sperem

[Dora]

Per oggi...

Allora ... lo so che non è quello che aspettiamo tutti con trepidazione ma, per adesso, accontentiamoci del report di Mascolini sulla presentazione di Mitsuyasu. 'Sta notte o domani, vedremo che cosa ha da dire Dale Ando (che sostituisce June).


Zinc Finger-Modified CD4-Cell Booster Transplant Working in Pilot Trial

51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), September 17-20, 2011, Chicago

Mark Mascolini

Transplant of CD4 cells modified in their zinc finger nuclease boosted CD4 counts in 9 people who achieved an undetectable viral load with antiretroviral therapy but had persistently low CD4 counts [1]. The procedure has been safe in the 9 study participants and normalized CD4/CD8 ratios in those with an abnormal ratio when this phase 1 trial began.

The principle behind SB-728-T is simple. This zinc finger DNA-binding protein transcription factor, developed by Sangamo Bioscience, disrupts the gene that makes CCR5 coreceptors sprout from CD4 cells [2,3]. When CD4 cells lack CCR5, HIV has a harder time infecting them. SB-728-T aims to propagate a population of CD4 cells resistant to HIV infection and thus to boost CD4 counts in poor CD4 responders and, perhaps, to make antiretroviral therapy unnecessary.

CD4 cells are collected from study participants and exposed once to SB-728-T, which generates cells lacking the CCR5 coreceptor. The cells are transduced with an adenovirus vector, expanded, then reinfused into the donor. Ideally, this zinc finger-modified population expands further in the body into a durable set of HIV-resistant CD4 cells.

Ronald Mitsuyasu (University of California, Los Angeles) and colleagues from other sites are conducting a phase 1 study that enrolled 9 antiretroviral-treated people with an undetectable viral load but a CD4 count still between 200 and 500. Study participants received 10, 20, or 30 billion modified CD4 cells. Mitsuyasu and coworkers saw study participants weekly for 1 week than monthly for the first 11 months. As in all gene therapy studies, he noted, safety follow-up will continue for 15 years.

The study group had a median age of 53, a median CD4 count of 384, and a median CD4 percent of 27.2%. Study participants had been infected with HIV for a median of 21 years.

At the time of this report, median follow-up duration stood at 337 days. So far there have been no serious adverse events. Of the 60 adverse events recorded, 53 were mild, 6 were moderate, and 1 (low back pain probably not related to the procedure) was severe. Two thirds of these adverse events occurred within 24 hours of the procedure, and all resolved.

Polymerase chain reaction determined that modified CD4 cells made up 0.2% to 2.8% of CD4s in the peripheral circulation at day 28, and those cells have persisted throughout follow-up. CD4 counts in these 9 people rose by a median of 163 cells through day 180. CD8 counts rose by a median of 33 cells over the same period. As a result, CD4/CD8 ratios returned to normal.

Modified CD4 cells could be detected in the rectal mucosa by day 14, a finding indicating that potentially HIV-resistant cells take residence in this critical site. However, the modified cells make up only a small proportion of rectal CD4 cells.

Mitsuyasu and colleagues calculated that the level of modified CD4 cells in their study is about 8-fold higher than in previous CD4-cell adoptive transfer studies. When pressed by attendees to explain this result, Mitsuyasu declined to offer a hypothesis, saying that the researchers are still analyzing data.

The investigators concluded that the modified CD4 cells engraft, expand, and persist for at least 1 year in people with HIV. They proposed that their preliminary data "suggest that SB-728-T offers the potential to reconstitute the immune system in HIV patients."

References
1. Mitsuyasu R, Lalezari J, Deeks S, et al. Adoptive transfer of zinc finger nuclease modified autologous CD4 T-cells to aviremic HIV-infected subjects with suboptimal CD4 counts. 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). September 17-20, 2011. Chicago. Abstract H1-375 (se a qualcuno fosse sfuggito, l'abstract tradotto si trova qui: http://www.hivforum.info/forum/viewtopic.php?p=38#p38).
2. Perez EE, Wang J, Miller JC, et al. Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008;26:808-816.
3. aidsmeds.com. SB-728-T. http://www.aidsmeds.com/archive/SB-728-T_2574.shtml.




La fonte la metterò appena questo report sarà pubblicato da Natap.

[Eilan]

Diciamo che al momento è un'altra piccola conferma, certo aggiunge poco a quanto già sapevamo, inoltre non si sbilanciano giustamente, però a me che sono profana, anche quell'aumento dei cd8 pur in assenza (in questo studio) di correlazione tra cd8 e viremia, mi incoraggia, hanno pur sempre una funzione citotossica.
Però un follow-up che durerà 15 anni, al tempo stesso mi rassicura e mi sconcerta pure, sarà che le sorpresine son sempre dietro l'angolo, e questa è una tecnica che comunque ''modifica'' qualcosa ma sarà solo il tempo giudice estremo.

[HLAB5701]

As in all gene therapy studies, he noted, safety follow-up will continue for 15 years.

Scusa, ma questo cosa implica? che per 15 anni la tecnica non sarebbe disponibile se non al massimo in via caritatevole per i casi disperati?