When the human immunodeficiency virus (HIV) was identified as the cause of the mysterious immune system depletion characterized by horrific vulnerability to infection, multiple dreadful symptoms and ultimately death, the world panicked. The medical and research communities were taken by surprise. Nothing could be said or done to help the agonizing victims or prevent their imminent death. It took a few years to introduce the first HIV drug, a nucleoside reverse transcriptase inhibitor. This milestone was followed by the development and marketing of non-nucleoside reverse transcriptase inhibitors, then a third class antiretroviral protease inhibitors (PIs). As HIV continued to reproduce and resistant variants of the virus emerge, It became necessary to combine the antiretroviral drugs in what has become known as highly active antiretroviral therapy (HAART). Indeed, the HAART combination resulted in profound reductions in AIDS morbidity and mortality.
The Increased familiarity and experience with the HIV and with the HIV drugs led to the development of antiretroviral drugs that could be taken once or twice daily as well as combinations of drugs in one tablet. These improvements resulted in easier use, hence, improved compliance and increased survival. Studies aiming at further improving HIV treatments never stopped. Recently, one of the studies demonstrated that in asymptomatic patients with higher CD4+ T cell counts, early initiation of HAART further improves survival.
Despite the promises of HAART, HIV treatment, nevertheless, is still fraught with problems. Toxicities arising from long-term use, high potential for drug interactions, and viral resistance still pose threats to many patients. Recognizing the fact that the approved drugs do not eradicate HIV infection, but merely suppress viral replication, sometimes to levels undetectable, necessitated new approaches that would increase treatment options. Blocking HIV entry into lymphocytes and macrophages became a priority target. However, the ideal options have been regimens that would induce the host immune system to eradicate HIV, or to increase cells’ resistance to the virus.
Scientists’ hopes of preventing HIV from entering host cells were realized first with the development of the drug, enfuvirtide, which binds to an HIV envelope glycoprotein, preventing the virus from fusing to the external surface of the host cell. The discovery that HIV attaches to host cell receptors (co-receptors), CCR5 and CXCR4 and that these transmembrane G protein-coupled receptors are critical for HIV entry into the cells, led to the discovery and development of therapeutics that would block CCR5, thereby prevent HIV from gaining access to the cells. Maraviroc, which binds to CCR5, was the first entry inhibitor to be developed with this mechanism of action. The approvals of enfuvirtide and maraviroc have provided additional treatment options for HIV infected patients. Still, sustained treatment with these drugs is required to prevent reactivation of the virus and disease progression, which subjects the patients to adverse effects and the drugs to viral resistance.
It seemed that learning from nature might prove to bring a near answer to the HIV tragedy. A population of individuals who demonstrated immunity to HIV infection despite multiple exposures to the virus has been identified. These individuals have been found to have a natural mutation, CCR5delta32, resulting in the expression of a shortened (truncated) and non-functional CCR5 protein. Scientists also found out that mutation in one of the two copies of the CCR5 gene kept HIV in check without drugs when the carriers of this one copy mutation contracted the virus.
In December 2010 journal Blood reported that an AIDS patient who had leukemia received a bone marrow transplant from a “matched” donor with this delta-32 CCR5 mutation. Transfer of the hematopoietic stem cells from the bone marrow of the delta-32 donor provided a self-renewable and potentially lifelong source of HIV-resistant immune cells in the recipient. To the specialists’ surprise, when the patient discontinued all antiretroviral drugs, CD4 counts increased and viral load dropped to an undetectable level.
These true stories opened the biotechnology firm Sangamo’s (NASDAQ:SGMO) eyes. The firm realized that its technology would enable it to mimic Nature. This firm was established around a technology based on engineering proteins that nature uses to control gene expression in living organisms from yeast to humans. The engineered proteins (DNA transcription factors), which are known as finger DNA-binding proteins (ZFPs) have two domains: the first is the ZFP portion that recognizes and specifically binds to a particular DNA sequence and the second is a functional domain. When the functional domain is brought into close proximity with a gene, it induces biologic effects that vary from activation, to repression, modification, correction, disruption, and addition.
Indeed, Sangamo used its ZFN-mediated editing technology to replicate the naturally occurring human mutation in CCR5 that renders individuals largely resistant to infection with the most common strain of HIV. Sangamo’s approach comprised removal of CD4+ T-cells from the blood of immunologic non-responders HIV-infected subjects who are currently on HAART, having undetectable levels of virus but suboptimal CD4+ T-cell counts. These CD4+ T-cells were then treated with Sangamo’s ZFNs that modify the DNA sequence encoding the CCR5 gene. The process has, indeed, generated CCR5-modified, autologous T-cell product (SB-728-T), which was infused in HIV/AIDS patients.
The data were stunning. The approach proved to be safe, as infusion of SB-728-T was well tolerated. The CCR5-modified cells successfully engrafted in all subjects and resulted in a durable improvement in total CD4+ T-cell counts in five of six of the subjects analyzed. Five of the six subjects exhibited sustained improvements in their CD4:CD8 T-cell ratio, which is an indicator of immunologic health. The ZFN-CCR5-modified cells exhibited normal T-cell growth kinetics and trafficking and underwent selective expansion in the gut mucosa, a major reservoir of virus in the body, suggesting that the cells were resistant to HIV infection.
Aren’t these the first steps on the road to developing an HIV/AIDS "functional cure?"
Providing AIDS patients with a protected CD4+ T-cell population resistant to HIV infection has been the dream that had yet to come true. This dream seems to materialize at Sangamo’s hands, as the data from experimentation were very encouraging. Dale Ando, M.D, Sangamo's vice president of therapeutic development and chief medical officer said it all when he stated: “The data represent an early validation of the feasibility of Sangamo’s gene modification approach for the treatment of HIV/AIDS.” “We have confirmed that we have a scalable manufacturing process and that from a single apheresis we can manufacture doses of SB-728-T of 10 to 30 billion cells. We have also learned that a single infusion of these cells is well tolerated and that the cells engraft, multiply and persist in the body. The modified cells behave like unmodified cells and traffic to the gut mucosa. In addition, we observed selective expansion of ZFN-modified cells in the gut mucosa, a major reservoir of HIV in the body, suggesting that these cells are protected from HIV and selectively enrich in the presence of the virus. The data also underscore our decision to expand our clinical studies to populations of HIV-infected individuals that have active viral replication and thus higher viral loads and retain immune reactivity to HIV. From such studies we will be able to assess the effect of ZFN-CCR5-modified T- cells on overall T-cell numbers and the course of the viral infection."
For more data go here.
What do we think?
We think what has been realized is a no less than a breathtaking breakthrough. The data are preliminary, but solid and unprecedented. Besides the hope they gave HIV victims, they offered proof of and validation of Sangamo’s Zink finger technology. We sincerely believe that this technology is on its way to offering the first wave of cures for many diseases that have yet to find a safe and effective treatment.
Disclosure: We're long Sangamo.