史无前例:美国首次临床基因试验性治疗表明有望促进抗艾滋病毒和抗癌症效果

% k: Y  b- b# b# s. I/ A2 XTrial Gene Therapy Shows Promising Results Against HIV And Cancer
试验性基因治疗显示有望促进抗艾滋病毒和抗癌症效果
作者: David L. DiGiusto, Amrita Krishnan, ETC
% x. Q& H6 Q5 N* T杂志: Sci Transl Med, 16 June 2010: Vol. 2, Issue 36, p. 36ra43
6 V% {7 G/ R; i# |) ?% H
4 L  {8 M; T, UIn the US, a small clinical trial of RNA-based gene therapy where patients were treated with genetically engineered versions of their own stem cells has shown for the first time that anti-HIV genes can persist in people with AIDS-related lymphoma: the researchers hope that the gene therapy research may eventually yield a cure for both the cancer and the HIV infection.

You can read about the study, led by researchers at the City of Hope Cancer Center in Duarte, California, in a paper issued online on 16 June in the journal Science Translational Medicine.

AIDS patients who develop lymphoma, a cancer of the immune system, are often treated with autologous HCT (hematopoietic cell transplantation), a stem cell treatment that replaces diseased bone marrow with healthy, functioning cells.

2 s7 F# O8 R4 h, c  U; QThis puts the lymphoma in remission but does not address the underlying HIV infection that most likely caused it, leaving HIV-positive patients on lifelong antiretroviral treatment to which they may one day become resistant.
+ \# V3 Z/ s7 d  H0 o- x! h. E* e
) B3 V& R! d: f3 l; gSo in this investigational study, senior author Dr John Zaia, Aaron D. and Edith Miller Chair in Gene Therapy and chair of virology at City of Hope, and colleagues, treated four patients undergoing the standard HCT with an extra procedure as a first step toward a possible HIV "hematopoietic cell-based" gene therapy.

4 t) Y  Y5 {+ F( e6 w5 M; q. O: EThey took healthy blood stem cells from the four patients, and modified them to include three anti-HIV ribonucleic acids (RNAs) that block HIV from infecting new cells.
( p  D; I) F' P" d. _" X
8 e1 l) Z* g2 O" \( {  {5 C& BThey then infused the modified stem cells, mixed with normal stem cells, back into the patients, and took regular blood samples to see how long the modified stem cells persisted in the blood of the treated patients. The researchers said none of the patients reported any side effects from the treatment.

9 Z# ?2 ?# r  U0 B& f( yZaia told the press that:

"We still see evidence that the patients are producing the therapeutic genes, including the siRNA, as long as two years after transplant."
4 \$ l+ w- H, L
: N& g. v4 d6 {7 dHe and his colleagues concluded that:
( A. ]/ c- s: S5 k
"These results support the development of an RNA-based cell therapy platform for HIV. "

The gene therapy that the researchers developed at City of Hope used ribozymes and "small interfering" RNA (siRNA), short strands of RNA to selectively silence specific genes against HIV infection. (In the paper the authors wrote that they created siRNAs to express three anti-HIV functions: CCR5 ribozyme, tat/rev short hairpin RNA and TAR decoy).

  f) O4 x+ \: X: SThe CCR5 ribozyme molecule stops the patient's white blood cells producing CCR5, a protein that HIV uses to get into host cells. Without CCR5 for the HIV to rob, the patient's immune cells can effectively resist HIV and prevent infection.

8 A  _9 p5 g! g2 W8 b5 W$ h" pThe siRNA also inactivates the HIV directly, while the TAR decoy component sequesters the HIV regulatory Tat protein from the virus.

In a statement the researchers said the object was to "reboot" the immune system to recognize and target HIV with a response that lowered the viral load.
& u2 e6 e! S5 B8 C0 T6 x
Lead author Dr David DiGiusto, professor of City of Hope's Department of Hematology and Hematopoietic Cell Transplantation, said:

9 g1 U9 ~- F6 r( I"While highly active antiretroviral drugs have managed to turn HIV infection from an immediate death sentence to a long-term manageable chronic condition, we are still seeking a cure."

' R7 f% r: J) A7 U! _3 t3 H"Our research and clinical trials are showing promise for this novel approach to treating HIV patients," he added.

Meanwhile the team is continuing with more research and clinical trials to improve the therapy so patients receive more genetically modified stem cells so they can develop greater resistance to HIV.

8 [, u  c+ w* [, ^2 C7 {"RNA-Based Gene Therapy for HIV with Lentiviral Vector-Modified CD34+ Cells in Patients Undergoing Transplantation for AIDS-Related Lymphoma."
5 n5 t. E# _7 r, C4 o1 Z) R) V
1 C& U1 A7 ^% v" I* i% |# QDavid L. DiGiusto, Amrita Krishnan, ETC
Sci Transl Med, 16 June 2010: Vol. 2, Issue 36, p. 36ra43
0 G" ]7 M# o0 N4 E  R4 Q/ X+ qDOI: 10.1126/scitranslmed.3000931