SB-728 is a ZFN-based approach for modification of the gene encoding CCR5, the major co-receptor used by HIV to infect cells of the immune system. Our first application is an autologous ZFN-CCR5-modified T-cell product (SB-728-T), which we are evaluating in an ongoing Phase 2 trial in Human Immunodeficiency Virus (HIV)-infected subjects.

We also have a clinical stage program to investigate this ZFN-mediated approach in hematopoietic stem progenitor cells (HSPCs).  With our collaborators at City of Hope and the University of Southern California, we have been granted a $14.5 million Disease Team Research Award by the California Institute for Regenerative Medicine (CIRM) to fund this program. In May 2014, Sangamo was also granted  a $5.6 million Strategic Partnership Award, a four-year grant that provides matching funds to support a clinical trial in HIV-infected individuals at City of Hope. This ZFN-CCR5-modified stem cell product (SB-728-HSPC) uses electroporation of mRNA to deliver the ZFNs. The Phase 1 clinical trial for SB-728-HSPC is expected to begin in 2015.

SB-728 for HIV/AIDS

Market Opportunity

HIV infection results in the death of immune system cells, particularly CD4+ T-cells leading to AIDS, a condition in which the body’s immune system is depleted to such a degree that the patient is unable to fight off common infections. Ultimately, these patients succumb to opportunistic infections or cancers. According to The United States Centers for Disease Control and Prevention (CDC), over 2.1 million people were newly infected with HIV in 2013 with an estimated 1.5 million people dying of AIDS-related illnesses in the same year. There are now over 35 million people living with HIV and AIDS worldwide. At the end of 2011 (the most recent data available), it is estimated that there were 1.2 million people living with HIV/AIDS in the United States alone, of which approximately 14% were unaware that they were infected. Approximately 48,000 new infections occurred in 2010, and more than 13,500 people with AIDS died in the United States in 2011.

Current Treatments and Unmet Medical Need

Currently available drugs do not cure HIV infection or AIDS. Current standard of care for HIV infection relies on a maintenance strategy of daily antiretroviral drugs designed to reduce viral replication and keep the infection in check. There are over 30 antiretroviral drugs approved by the FDA and almost all are designed to inhibit some stage of the viral replication pathway. These drugs fall into four major classes: reverse transcriptase inhibitors, integrase inhibitors and entry and fusion inhibitors.

As HIV reproduces, variants of the virus emerge, including some that are resistant to antiretroviral drugs. Therefore, doctors recommend that people infected with HIV take a combination of antiretroviral drugs, or ART. This strategy typically combines drugs from at least three different classes of antiretroviral drugs that can suppress the virus, even to undetectable levels, but they cannot eliminate HIV from the body. Hence, people with HIV need to take antiretroviral drugs continuously, which can be expensive and have significant undesirable side effects. There is no therapeutic approach available which protects CD4+ T-cells, reduces viral load and does not require continuous daily dosing.

Sangamo’s Therapeutic Approach

Our therapeutic approach aims to use our ZFN-mediated genome editing technology to replicate a naturally occurring human mutation which renders individuals largely resistant to infection with the most common strain of HIV. CCR5 is a co-receptor for HIV entry into T-cells and if CCR5 is not expressed on their surface HIV infects them with lower efficiency.

A population of individuals that is immune to HIV infection, despite multiple exposures to the virus, has been identified and extensively studied. The majority of these individuals have a natural mutation, CCR5 delta-32, of both of their CCR5 gene copies (homozygous), resulting in the expression of a shortened, non-functional CCR5 protein. This mutation appears to have no observable deleterious effect. Individuals who carry the CCR5 delta-32 mutation in only one of their two CCR5 gene copies (heterozygotes), tend to take longer to develop AIDS and are calssified as so-called "long-term non-progressor." In addition, a study published in Blood in December 2010 reported an effective cure when an AIDS patient with leukemia received a bone marrow transplant from a “matched” donor who was homozygous for this delta-32 CCR5 mutation. This approach transferred the hematopoietic stem cells (HSCs) residing in the bone marrow from the delta-32 donor, and provided a self-renewable and potentially lifelong source of HIV-resistant immune cells. After transplantation, the AIDS patient was able to discontinue all anti-HIV drug treatments (ART), CD4 counts increased and viral load dropped to an undetectable level, demonstrating effective transplantation of protection from HIV infection. The subject remains off ART and is widely considered to be cured of his HIV infection.

We are using our ZFN-mediated genome editing technology to disrupt the CCR5 gene in cells of a patient’s immune system to make these cells permanently resistant to HIV infection. The aim is to provide a population of HIV-resistant cells that can fight HIV and opportunistic infections thereby  mimicking the characteristics of individuals that carry the natural CCR5 delta-32 mutation.