HIV. A brief history
There has been a lot of promising cure research in the past 40 years, but problem still seems unresolved. With all the attempts of the early drug treatments or vaccines, the scientists still can’t yet completely remove HIV from the body.
Back in 2007, a single patient (the s.c. “Berlin patient”) was known to have achieved full HIV eradication. After a long-term HIV infection, this patient has developed acute myeloblastic leukemia (AML), and underwent the allogeneic hematopoietic stem cell transplantation (allo-HSCT) performed from a donor harboring a rare Δ32 mutation of the CCR5 receptor.
The CCR5 receptor plays crucial role in the HIV pathogenesis, mediating the entry of virus to the cell. People with naturally occurred mutation of both CCR5 alleles are non-susceptible to HIV infection. It took over a decade for another two cases of HIV cure to happen – today we call them the London and the Dusseldorf patients. This testifies difficulty of the treatment method on one hand, but the eventual efficiency of this approach on the other.
According to WHO, over 10,000 of human diseases are known to be monogenic (MD). These monogenic diseases include rare diseases such as:
o Primary immune deficiencies
o Lysosomal storage diseases & Metabolic diseases
o The HSC pathologies
The total global prevalence of all monogenic disorders at birth has been calculated to be several percent, which means hundreds of thousands of new cases every year. This disease group creates a heavy burden on the global healthcare system. Most monogenic disorders have no effective treatment options today. For some of them, however, allogeneic haematopoietic stem cell transplantation offers the only hope for lifelong cure, but because of a high risk of complications this method can not be considered as optimal and new methods are greatly needed.
AGCT is working on innovative treatment approaches based on genome editing of hematopoietic stem cells (HSC).
The CCR5 Δ 32 homozygotes make <1% of Caucasian population, minimizing chances for finding an HLA-compatible donor with such a genetic defect.
We believe that the groundbreaking and exciting field of genome editing will allow us to induce the ССR5 genetic change in human cells and develop resistance to HIV. The TALEN based approach developed by the AGCT team allows to achieve specific and safe CCR5 gene knockout and generation of HIV resistant immune system.
Hematopoietic stem cells (HSCs) are among the most promising targets for the gene manipulation since they comprise a pluripotent progenitor population of stem cells giving rise to a variety of blood cells, gaining a lifetime-long generation of immune cells resistant to HIV.
The mentioned case of HIV eradication after HSCT from the CCR5-Δ32 homozygous donor (the “Berlin patient”) confirms further prospective for HSC modification aiming at CCR5 gene silencing for HIV cure.
In this product, the TALEN platform is used for CCR5 knockout in patients T-lymphocytes. While T-lymphocytes are the main target for HIV infection, important features of these cells are long circulation period and ability for proliferation upon activation. Because of this, even the small CCR5 deficient cell population gains selective advantage over ordinary T-cells. This phenomenon helps to achieve immune control over disease and open the way for functional cure. The infusion of T-cells is not requiring the high dose chemotherapy, thus is safe and may be administered several times for further increase of HIV-resistant T-cell population and intensity of antiviral immunity.