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

Ricerca scientifica finalizzata all'eradicazione o al controllo dell'infezione.
Dora
Messaggi: 7491
Iscritto il: martedì 7 luglio 2009, 10:48

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

Messaggio da Dora » domenica 18 settembre 2011, 17:33

HLAB5701 ha scritto:
Dora ha scritto: 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? :shock:
Non credo. Però che il follow-up debba essere lungo è stabilito dall'FDA. Ho trovato un documento (il primo che ho trovato, del 2002; possibile che esista qualcosa di più recente e aggiornato a vettori che NON si integrano in permanenza, come il rinovirus utilizzato da Sangamo (*)), in cui si sostiene:

Current long-term follow-up published guidance

In current guidance documents, FDA’s long-term testing and subjectmonitoring recommendations focus on those subjects treated with retroviral vectors. FDA currently has published no specific recommendations for longterm follow-up of subjects treated with any other classes of gene transfer vectors.
One rationale for recommending long -term follow-up in subjects participating in gene transfer clinical trials using retroviral vectors is based on the fact that these vectors are known to integrate into the genome. The consequences of life-long exposure to the gene product or to the introduced genetic sequences can only be assessed through the long-term follow-up of these patients.
Another reason for long -term follow-up efforts in studies using retroviral vectors is that use of retroviral vectors carries the potential for exposure of patients to replication competent retroviruses (RCR). Retroviral infection, including HIV infection, in many species can result in latent infection with disease appearing years later. In 1993, a report of lymphoma in 3 out of 10 immunosuppressed non-human primates that received retrovirally transduced bone marrow cells with high titer RCR (Donahue, R. E. et al. 1992. Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer. J. Exp. Med. 76:1125-1135) led to recommendations for patient testing for evidence of RCR infection in a 1993 guidance. (...)

Impact of vector characteristics on the approaches to long term follow-up

Current medical and regulatory systems are not well designed to track individual gene therapy study subjects over long periods to identify very late treatment related toxicities (i.e., years later) and to examine causal association with the gene therapy.
Prior to consulting an advisory committee and considering new policy in this area, FDA did substantial background work investigating the types of longterm concerns, the classes of gene therapy products to which they apply, and the feasibility of various approaches to collecting such data.
In these efforts, we gave careful consideration and deliberation not only to the safety issues that need to be addressed but also to the practical difficulties in reliably collecting such data (see section 3.1.2.1).
To detect latent or long-term effects, clinical follow-up for extended periods of time is important. FDA convened the BRMAC on November 16-17, 2000, April 5-6, 2001, and October 24, 2001, to discuss issues pertaining to the long-term follow-up of gene transfer study participants. Deliberations of the committee largely focused on three areas: what types of vectors raised concerns warranting long-term follow-up (briefly summarized in this section), what types of clinical information should be obtained in long-term follow-up (next section), and how such information should be obtained (section 3).
In addition to reviewing the adequacy of current recommendations for studies that use retroviral vectors, BRMAC was asked to consider the appropriate long-term follow-up in conjunction with the growing use of other non-retroviral, RNA- and DNA-based delivery mechanisms (vectors) for which there is no FDA guidance. Briefing materials for BRMAC members included information on vector design, product characterization, preclinical models, known and hypothetical risks associated with vector class and vector properties, procedures for reporting adverse events, the value of centralized database, limitations or barriers to effective data collection and reporting, and types and time courses of late adverse events associated with other types of therapies and infections.

The BRMAC deliberated on the risks associated with RNA- and DNA-based vectors and the various factors that contributed to those risks. They noted that all gene therapy vector systems carry sufficient concerns about long-term side effects to warrant some level of long-term follow-up, but certain categories of gene transfer vectors warranted more attention. BRMAC pointed out vector classes of particular concern included: 1) vectors with the potential to integrate; 2) vectors with the potential to replicate; 3) vectors with altered tropisms; and, 4) vectors with long latency. Some additional vector characteristics were thought to have significant impact on the degree of long - term risk.
For example, integrating vectors have the potential to initiate neoplastic processes depending upon the site of integration or presence of strong promoter/enhancer elements present in the gene transfer vector. Host characteristics such as the immune status of recipient, the route of administration (intra-venous, intra-arterial, subcutaneous, etc.), and the type of cell targeted for transformation (ex-vivo transformation of stem cell, cells capable of division and lasting life cycle vs. irradiated cells, etc) were also discussed and felt to be influential factors.
Recognizing the large number of factors that could influence the nature and degree of long -term risks in any given study, the BRMAC was reluctant to endorse a specific global approach to long-term follow-up based on vector characteristics. Instead, BRMAC recommended that FDA scientists apply scientific principles and judgment to determining appropriate follow-up. (Gene Therapy Patient Tracking System, pp. 9-12)



(*) Ecco, lo sapevo che doveva esserci qualcosa di più recente. Solo che è lunghissimo e non ho tempo di leggerlo: Guidance for Industry Gene Therapy Clinical Trials – Observing Subjects for Delayed Adverse Events.



Dora
Messaggi: 7491
Iscritto il: martedì 7 luglio 2009, 10:48

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

Messaggio da Dora » domenica 18 settembre 2011, 17:54

E' uscito su Bloomberg mezz'ora fa un articolo in cui non si dice ancora nulla di serio, ma si riportano delle dichiarazioni di Tebas durante un'intervista che gli è stata fatta a margine del congresso. Queste le cose rilevanti:

The most common side effect cited in the gene therapy study was a persistent smell of garlic, the researchers said. After the therapy, one patient who naturally had one copy of the mutant DNA maintained undetectable levels of HIV without drug use, the study found.

Questa, invece, una dichiarazione telefonica di Edward Lanphier, CEO di Sangamo:

We see a significant anti-viral effect (...). That’s the big punchline here.



Fonte: Sangamo’s Blood-Cell Gene Therapy Fights HIV Without Drugs, Study Shows



skydrake
Messaggi: 9921
Iscritto il: sabato 19 marzo 2011, 1:18

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

Messaggio da skydrake » domenica 18 settembre 2011, 18:29

Dora ha scritto:The most common side effect cited in the gene therapy study was a persistent smell of garlic
:lol: :lol: :lol: Mi trattengo a far battute



Dora
Messaggi: 7491
Iscritto il: martedì 7 luglio 2009, 10:48

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

Messaggio da Dora » domenica 18 settembre 2011, 20:21

skydrake ha scritto:
Dora ha scritto:The most common side effect cited in the gene therapy study was a persistent smell of garlic
:lol: :lol: :lol: Mi trattengo a far battute
Ridi, ridi, ben venga l'aglio!! :lol:
Fra parentesi, se accade come nel trapianto di staminali, dopo qualche ora (forse qualche giorno? non ricordo bene) l'odore svanisce.



Dora
Messaggi: 7491
Iscritto il: martedì 7 luglio 2009, 10:48

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

Messaggio da Dora » domenica 18 settembre 2011, 20:30

L'abstract di June ancora non c'è. C'è però questo comunicato stampa nel sito di Sangamo. Lo riporto integralmente, anche se i dati di Mitzuyasu li conosciamo già, perché ci sono considerazioni interessanti su tutti i trial nel loro complesso:

Sangamo BioSciences Announces Presentation of Groundbreaking Clinical Data From ZFN Therapeutic for HIV/AIDS at ICAAC 2011

RICHMOND, Calif., Sept. 18, 2011

Sangamo BioSciences, Inc. (Nasdaq: SGMO) announced that data from its Phase 1 clinical programs to develop SB-728-T, a novel therapeutic approach for the treatment of HIV/AIDS, were discussed in two presentations at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). The meeting is being held in Chicago from September 17-20, 2011.

"The data obtained in our treatment interruption studies are very exciting and represent significant progress toward a 'functional cure' for HIV/AIDS," said Carl June, M.D., Director of Translational Research at the Abramson Family Cancer Research Institute at the University of Pennsylvania School of Medicine, who with Pablo Tebas, M.D., is an investigator in the Phase 1 studies of SB-728-T at that institution. "The statistically significant relationship between estimated modification of both copies of the CCR5 gene and viral load during the treatment interruption suggests that the next step is to increase the frequency of the modified cells in HIV-infected patients with the ultimate hope that if we do, we will achieve a 'functional cure' and eliminate the need for continued HAART."

In an oral presentation made on Saturday, September 17th at ICAAC, data were presented from all dosing cohorts of Sangamo's Phase 1 dose escalation study (SB-728-902) in subjects on highly active antiretroviral therapy (HAART) who entered the study with CD4+ T-cells counts of <500 cells/mm3 after several years of therapy ("immunologic non-responders"). A presentation made today described data from the second cohort of a Phase 1 clinical study of the same drug, conducted at the University of Pennsylvania and Albert Einstein College of Medicine, in subjects who entered the study with CD4+ T-cell counts of >450 cells/mm3 and underwent a treatment interruption (TI) of HAART following treatment with SB-728-T.

Data from these presentations demonstrate:

A statistically significant relationship (p<0.05) between suppression of HIV viral load (VL) and calculated levels of circulating CD4+ T-cells that have undergone biallelic modification (i.e. modification of both copies) of the CCR5 gene in SB-728-T-treated individuals who underwent a TI. CCR5 is the major co-receptor used by HIV to infect cells of the immune system.
The VL of one SB-728-T treated-subject decreased to undetectable levels during a TI. This subject was found to be heterozygous for the CCR5 delta-32 gene mutation, i.e. half that subject's CCR5 genes were naturally disrupted
.
Confirmation and extension of previous observations of unprecedented improvements in overall CD4+ T-cell counts and CD4+ : CD8+ T-cell ratios, as well as engraftment, expansion, trafficking and persistence of the ZFN modified cells.
SB-728-T treatment continues to be safe and well tolerated.

"We are very encouraged by both this early demonstration of an antiviral effect of SB-728-T as well as the marked improvement in the overall CD4+ T-cell counts in treated subjects in the SB-728-902 trial," said Ronald Mitsuyasu, M.D., Professor of Medicine, David Geffen School of Medicine at UCLA and a principal investigator of Sangamo's SB-728-902 study. "While their viral loads are well controlled on HAART, these subjects experienced incomplete restoration of their T-cell counts. Improvement and preservation of the immune system is of paramount importance in HIV and those seen in this study show an improvement over that seen after several years of HAART."

"There is no other drug that has been shown to have the same dramatic effect on the immune system in this setting," stated Dale Ando, M.D., Sangamo's vice president of therapeutic development and chief medical officer. "SB-728 treatment results in unprecedented improvement in immune system health as measured by increased CD4+ T-cell levels and improved CD4+: CD8+ T-cell ratios, even in subjects that entered the trial with poor CD4+ counts. Moreover, the interesting kinetics in viral load that we observed in the first few subjects that underwent a treatment interruption has been borne out and has allowed us to correlate a statistically significant effect of the rate of biallelic ZFN-modification of the CCR5 gene on viral load during treatment interruption."

"Data presented this weekend at ICAAC suggest that, with sufficiently high levels of circulating biallelically modified cells and good engraftment, SB-728-T can provide a 'functional cure' for HIV," said Geoff Nichol, M.B., Ch.B., Sangamo's executive vice president of research and development. "We continue to collect valuable data about the parameters essential for optimization of this novel drug candidate. Based on these data, Sangamo plans to continue to expand our clinical trials and carry out confirmatory studies in subjects who are natural heterozygotes for the CCR5 delta-32 mutation. We will also explore other mechanisms to enhance engraftment and maximize the impact of the HIV resistant cells on viral load and the overall immune system of HIV patients. The ground-breaking clinical data that we and our collaborators are generating continue to validate our highly specific ZFN technology as a platform for development of novel therapeutic products."

Clinical Trial Data Summary

Abst.# H2-794a: "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" Presenters: Dale Ando, M.D., Vice President, Therapeutic Development and CMO and Geoffrey Nichol, M.B., Ch.B., Executive Vice President, Research and Development, Sangamo BioSciences, Inc.

In a late-breaker session on Sunday, September 18, 2011 data were presented from the six subjects enrolled in cohort 2 of the Phase 1 clinical trial of SB-728-T conducted at the University Pennsylvania and Albert Einstein College of Medicine. These subjects entered the clinical trial with CD4+ T-cell counts of >450 cells/mm3 and underwent a twelve week HAART TI four weeks after treatment with a single dose of SB-728-T.

The data demonstrate that:

A statistically significant relationship between VL and the calculated percentage of circulating CD4+ T-cells that have undergone ZFN-mediated modification of both copies (biallelic) of the CCR5 gene within a cell (P= 0.0001 for VL at the end of TI, and 0.037 for area under the curve of VL over the TI period).
A 0.8 to >2.0-log reduction in VL from peak during TI was observed in the 3 of 6 subjects with the highest estimated circulating levels of cells with biallelic modification.
One subject's VL decreased to undetectable levels such that the subject was considered to be aviremic at the end of the TI period
. This subject entered the study carrying the natural CCR5 delta-32 mutation on one copy of his CCR5 gene resulting in an estimated percentage of biallelically-disrupted CCR5 genes that was twice that of subjects entering the study with wild type CCR5 genes.
Persistent engraftment of ZFN-modified T-cells, overall improvement in total CD4+ T-cell levels and CD4+:CD8+ T-cell ratios as well as normal trafficking of the cells and the safety and tolerability of the treatment.

These data provide important new information of the design of future clinical studies including enhanced engraftment strategies.

Abst.# H1-375: "Adoptive Transfer of Zinc Finger Nuclease (ZFN) Modified Autologous CD4+ T-Cells to Aviremic HIV-Infected Subjects with Suboptimal CD4+ Counts" Presenter: R. Mitsuyasu, M.D., Professor of Medicine, David Geffen School of Medicine, UCLA.

In a presentation on Saturday, September 17, 2011, Dr. Mitsuyasu discussed data from the full complement of subjects in Sangamo's ongoing Phase 1 dose-escalation study (SB-728-902) in aviremic subjects with CD4+ T-cell counts <500 cells/mm3. These subjects are often classified as immunologic non-responders because, while they have their virus levels well-controlled by HAART, their immune systems have not responded well and levels of CD4+ cells remain depressed.

The data demonstrate that:

SB-728-T is safe and well tolerated in this patient population with only mild, reversible symptoms typical of infusion reactions.
ZFN CCR5-modified cells engrafted, expanded, and persisted for the duration of the study to date (Median of 337 days, range: 115-561).
The modified cells trafficked to the gut mucosa, an important reservoir of active HIV infection.
Notably, an increase in total CD4+ T-cells was observed in all subjects and a normalization of the ratio of CD4+:CD8+ T-cells, a measure of immunologic health, was observed in the majority of subjects that entered the study with a ratio below one. These immunologic improvements were persistent over the study period
.
These data confirmed and extended preliminary data that were previously reported from the first two dosing cohorts of the trial at the Conference on Retroviral and Opportunistic Infections (CROI) in March 2011.
In addition, data were presented from one subject in this trial who has undergone an extended treatment interruption one year after SB-728-T infusion and saw a VL reduction from peak during TI of >1-log, suggesting a potential antiviral effect of the treatment.

(...)



Dora
Messaggi: 7491
Iscritto il: martedì 7 luglio 2009, 10:48

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

Messaggio da Dora » domenica 18 settembre 2011, 23:16

Sto aspettando che tolgano l’embargo all’abstract, ma non credo ci darà più informazioni rispetto al comunicato stampa di Sangamo. Quindi, una brevissima sintesi di quel che sappiamo.

Tralascio per il momento il discorso sui CD4, perché che quelli modificati siano stati ben tollerati, abbiano attecchito, si siano andati a posizionare dove serviva (soprattutto nel GALT) e che si siano visti degli aumenti in valori assoluti nei pazienti immunological non responders lo sapevamo già fin dal CROI. In più, ci viene detto che a questi pazienti è migliorato anche il rapporto CD4/CD8.

Quello che è nuovo è la correlazione statistica (p<0.05) fra la soppressione della viremia dopo interruzione della HAART e la modificazione stimata di entrambe le copie del gene CCR5 (“modificazione biallelica”).
In particolare, la viremia di un paziente è diminuita al punto di diventare irrilevabile dopo che la terapia era stata sospesa (ed è rimasto senza farmaci per un anno) e si è visto che questo paziente era di suo eterozigota CCR5delta32, ma dopo il trattamento la metà dei suoi geni che codificano per il CCR5 erano stati distrutti dall’SB-728-T.

In 3 pazienti su 6 (quelli con i maggiori livelli stimati di cellule con la modificazione biallelica) si è vista una riduzione della viremia da 0.8 a più di 2 log, sempre dopo la sospensione della HAART.

Da questo June e colleghi hanno dedotto che il trattamento abbia un “potenziale effetto antivirale”.

Il prossimo passo sarà di “aumentare la frequenza delle cellule modificate”, nella speranza di arrivare a una cura funzionale che permetta di eliminare la necessità di assumere antiretrovirali in modo continuativo.




thelondonsuede
Messaggi: 742
Iscritto il: domenica 18 marzo 2007, 18:19
Località: SARANNO POI CAZZI MIEI UHUHUUHUHU
Contatta:

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

Messaggio da thelondonsuede » lunedì 19 settembre 2011, 12:08

si beh bisogna vedere quanto ci vuole prima che entri commercio se ci vogliono 15 anni faccio in tempo a voltare i piedi a uscio :lol: :lol: :lol: 8-)



Aragorn

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

Messaggio da Aragorn » lunedì 19 settembre 2011, 12:14

Con quello che risparmierebbero gli stati di tutto ilmondo senza Haart... Spero che questo velocizzi il tutto!



Dora
Messaggi: 7491
Iscritto il: martedì 7 luglio 2009, 10:48

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

Messaggio da Dora » lunedì 19 settembre 2011, 12:26

thelondonsuede ha scritto:si beh bisogna vedere quanto ci vuole prima che entri commercio se ci vogliono 15 anni faccio in tempo a voltare i piedi a uscio :lol: :lol: :lol: 8-)
Aragorn ha scritto:Con quello che risparmierebbero gli stati di tutto ilmondo senza Haart... Spero che questo velocizzi il tutto!
15 anni è il tempo in cui dovrebbero restare in osservazione i pazienti del trial per essere sicuri che le modificazioni genetiche apportate ai loro CD4 non causino danni gravi.
Tutt'altro discorso è la commercializzazione del farmaco. Se ricordate, a febbraio, dopo il CROI, Sangamo aveva prospettato di mettere in commercio l'SB-728-T nel giro di tre anni.
Quanto ai costi, al momento sono altissimi: circa 90.000 dollari (per fare un confronto, un trapianto di staminali ne costa circa 250.000). Ma è chiaro che i costi verrebbero abbattuti nel momento in cui il farmaco potesse essere prodotto in quantità.

In ogni caso, vorrei ricordarvi che siamo ancora alla fase I e che i dati dopo la sospensione della HAART sono parziali: per esempio, che cosa è successo ai 3 pazienti che non hanno avuto una diminuzione della viremia fra 0.8 e 2 log? Dopo quanto tempo hanno dovuto tutti riprendere la terapia?
E queste sono solo le prime domande che mi vengono in mente mentre preparo il pranzo. ;)



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