| Anti-CCR5 gene targeting |
Ref |
Evidence |
Benefits |
Limits |
Natural Delta32
homozygosis |
[2-6] |
Spontaneous mutation occurring
in 4-18% of European and
Askenazi Jews people.
Not found in Asian and Pacific
indigens. |
Lack of CCR5 surface
expression.
No signs of immune alterations.
Resistance to R5 HIV infection. |
No resistance to X4 or dual R5/X4
strains.
High sensitivity to West Nile virus
and tick-borne encephalitis. |
Transplantation of CCR5-/-
cells (HST or T
lymphocytes) |
[19, 20,
29] |
Clinical infusion of modified
cells in patients undergoing
cytoreductive treatment. |
Resistance to HIV infection.
Long-term cell survival
GI mucosal colonization.
Brain colonization
Reduction of HIV reservoirs ?
Heritable DNA modification.
Definitive cell cure . |
Off-target genotoxicity (e.g. CCR2).
Oncogenesis.
CXCR4 is required for HSC
maturation in bone marrow.
Multiple treatment cycles ?
Selection of resistant strains.
Mucosal efficacy? |
CCR5 and/or CXCR4 KO
by Zn-finger Nucleases in
T cells |
[29] |
Ex vivo transient expression of
viral vectors carrying ZFNs |
Resistance to HIV infection.
Mucosal protection?
Reduction of HIV reservoirs ?
Definitive cell cure ? |
Off-target toxicity
Insertional mutagenesis?
Lentivirus-induced activation or
mobilization of endogenous LTR?
Unknown long-term safety issues. |
CCR5 KO
by TALENs or CRISPRs in
T cells |
|
Preclinical study in mice
receiving ex vivo modified T
cells |
Lower off-target activity than
ZFNs. |
Double CCR5+CXCR4
KO
by ZFNs in T cells |
|
Ex vivo trial |
Total resistance to HIV
infection. |
| Ribozymes |
|
In vitro
Ex vivo trial |
Preventing CCR5 expression. |
Lentivirus-induced activation or
mobilization of endogenous LTR? |
Intrabodies-mediated
CCR5 intracellular
retention |
|
Ex vivo assay |
Preventing CCR5 expression.
Resistance to R5-HIV infection. |
Excess of intracellular protein
entrapment |
