The HIV problem
There are now more than 35 million people living with HIV and AIDS worldwide. In spite of the advent and broad implementation of active antiretroviral therapy (HAART) AIDS pandemics could not be slowed down. Since the discovery of the human immunodeficiency virus (HIV) over 30 years ago, the problem of AIDS and its frequent and most severe complication, oncological diseases, has become one of the most important social problems.
This problem is even more challenging for Russian Federation and ex-USSR countries (especially CIS). Development of radical treatment of HIV infection and its complications comprises a universally recognized worldwide challenge of scientific, clinical and social significance.
A brief history
Numerous attempts and efforts were undertaken in the last 30 years, but this problem still seems unresolved. All attempts of the early drug treatments or vaccines were noncurative for the HIV-infected patients.
Today, a single patient (the s.c. “Berlin patient”) is 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.
USING THE NATURAL WAY FOR HIV RESISTANCE&CURE
Unfortunately, the CCR5Δ32 homozygotes make ~1% of Caucasian population, making chances for finding an HLA-compatible donor with such a genetic defect making the chance of finding an HLA-identical CCR5 Δ32 homozygous donor extremely low.
Hopefully the new emerging and exciting field of genome editing can give hope for reiteration of natural way for resistance to HIV – the ССR5 genetic change. The TALEN based approach developed by AGCT team allows to achieve specific and safe CCR5 gene knockout and generation of HIV resistant immune system.
There are two project based on CCR5 knockout for HIV treatment:
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 for 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.
According to WHO, more than 10,000 monogenic diseases (MD) are currently explored. Known also as rare diseases, the total incidence of MD at birth is up to 1%, which means hundreds of thousands of new cases every year. This disease group creates a heavy burden to the global healthcare system. The are no current curative approaches for most of the MD. The only existing radical method of treating a number of diseases from this group is allogeneic stem cells transplantation. Because of high risk of complication, this method can not be considered as optimal and there is great need for introduction of new methods.
The scope of AGCT in the field of inherited diseases is development of innovative treatment approaches based on genome editing of hematopoietic stem cells (HSC).
- Primary immune deficiencies
- Lysosomal storage diseases & Metabolic diseases
- The HSC pathologies