I would gander a view that this was highly success
Post# of 148099
(Total Views: 644)
Posted On: 07/24/2024 10:43:15 AM
I would gander a view that this was highly successful, especially after reading this from your link provided. The barriers that prevent success are numerous. Maybe it's not a grand slam homerun, but maybe a homerun? I'm not sure but I think one could surmise that giving a patient Leronlimab in conjunction with an AAV delivered drug would boost the chance of success???
Immunological barriers to rAAV gene delivery
The rAAV protein capsid, its DNA genome and the protein product of the transgene can interact with host immune systems at multiple layers, posing substantial barriers to effective gene delivery and persistent gene expression (FIG. 5). The first barrier concerns the NAbs against the rAAV capsids that are identical or similar to the capsids of wtAAVs. NAbs in the blood circulation are found in a large portion of the human population owing to natural wtAAV infection and can effectively block rAAV gene delivery, especially following intravenous injection. The immune-privileged brain can tolerate a somewhat high NAb titre following a direct CNS delivery but is not completely shielded from circulating NAbs. Several strategies have been developed to overcome this barrier, such as plasmapheresis and using empty capsids as decoys, but they are not effective in tackling high-titre NAbs. Another approach is to engineer rAAV capsid by eliminating NAb-interacting epitopes. The effectiveness of these strategies under clinical settings remains to be tested. Currently, NAb screening and excluding seropositive subjects from enrolment remain necessary steps in many clinical studies.
immunological barriers to successful rAAv gene delivery.
The recombinant adeno-associated virus (rAAV) may encounter neutralizing antibodies (NAbs) that are widely found in the human population, which greatly compromises gene delivery , especially following intravascular administration. Furthermore, administration of rAAV can induce capsid-specific NAb generation (not shown). The rAAV capsid and genome may trigger innate immunity via activation of Toll-like receptor 2 (TLR2) and TLR9, respectively. Activation of innate immunity can further promote adaptive immune responses. The capsid undergoes proteasomal degradation, and the resulting peptides are presented by major histocompatibility complex (MHC) class I molecules to CD8+ T cells. The CD8+ T cell can exert destructive cytotoxic effects to eliminate rAAV-transduced cells, resulting in the loss of transgene expression. The transgene product can elicit a humoral immune response to generate transgene product-specific antibodies that can compromise therapeutic efficacy. AAV, adeno-associated virus.
Following rAAV administration, the vector capsid triggers a robust humoral immune response to generate NAbs, preventing re-administration in most cases. For applications likely requiring repeated dosing, transient B cell depletion upon the first injection and induction of immune tolerance by rapamycin may be considered. In addition, the capsid can trigger a cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, which may lead to the clearance of transduced cells and therefore loss of transgene expression. This phenomenon appears prominent in humans and is not readily modelled in animals. It should be noted that the CTL response mounted against the rAAV capsid is much weaker than those mounted against other viral vectors such as adenoviral vectors. CTL response caused by rAAV administration may compromise therapeutic efficacy over time but generally does not pose a major safety concern. Some muscle-targeting clinical studies suggest that regulatory T (Treg) cells may play a role in restraining the effect of CD8+ CTLs. Pharmacological suppression of CD8+ T cells with steroids is effective in managing liver CTL response following systemic rAAV delivery and ensuring long-term transgene expression. Inspired by the induction of endogenous Treg cells in muscle-directed rAAV gene therapy and their potential role in limiting CTL response, administering autologous Treg cells as an adjuvant to in vivo gene transfer may provide a powerful approach for modulating rAAV immunity.
The transgene may encode a protein that is foreign to the host, as is the case for gene replacement therapies in patients with a null genotype or gene addition therapies with vectored antibody-like molecules. The transgene product may therefore trigger both B cell-mediated and T cell-mediated adaptive responses to generate transgene product-specific antibodies and CTLs. Circulating antibodies may prevent lasting therapeutic efficacy. Likewise, anti-antibody responses are currently a major barrier for developing AAV vectored antibodies for infectious diseases. The transgene product-specific CTL response was reported in muscle-targeted clinical trials in liver-directed haemophilia trials. Establishing the necessary enrolment criteria could have helped to mitigate such a risk. Importantly, the tolerogenic ability of the liver also impacts rAAV gene transfer. The transgene product-specific immune tolerance induced by liver-directed rAAV gene delivery is dose-dependent and likely involves Treg cells. This endogenous immune modulation phenomenon can be harnessed to achieve stable transgene expression and therapeutic efficacy.
In addition to eliciting adaptive responses, the rAAV capsid and vector genome are also sensed shortly after delivery by the innate immunity through Toll-like receptor 2 (TLR2) and TLR9, respectively. This response leads to the production of pro-inflammatory cytokines and promotes the adaptive response. Self-complementary rAAV genomes or vector genomes with high content were shown to further enhance the immune response. Therefore, preventing TLR signalling by depleting CpG dinucleotides in the rAAV genome has the potential to enhance rAAV-mediated gene expression. Another promising strategy is to incorporate a TLR9-inhibitory DNA sequence, such as multiple copies of TTAGGG derived from human telomeres, into the rAAV genome to evade innate immune surveillance. This approach was reported to reduce the immune responses associated with rAAV delivery in mice.
Immunological barriers to rAAV gene delivery
The rAAV protein capsid, its DNA genome and the protein product of the transgene can interact with host immune systems at multiple layers, posing substantial barriers to effective gene delivery and persistent gene expression (FIG. 5). The first barrier concerns the NAbs against the rAAV capsids that are identical or similar to the capsids of wtAAVs. NAbs in the blood circulation are found in a large portion of the human population owing to natural wtAAV infection and can effectively block rAAV gene delivery, especially following intravenous injection. The immune-privileged brain can tolerate a somewhat high NAb titre following a direct CNS delivery but is not completely shielded from circulating NAbs. Several strategies have been developed to overcome this barrier, such as plasmapheresis and using empty capsids as decoys, but they are not effective in tackling high-titre NAbs. Another approach is to engineer rAAV capsid by eliminating NAb-interacting epitopes. The effectiveness of these strategies under clinical settings remains to be tested. Currently, NAb screening and excluding seropositive subjects from enrolment remain necessary steps in many clinical studies.
immunological barriers to successful rAAv gene delivery.
The recombinant adeno-associated virus (rAAV) may encounter neutralizing antibodies (NAbs) that are widely found in the human population, which greatly compromises gene delivery , especially following intravascular administration. Furthermore, administration of rAAV can induce capsid-specific NAb generation (not shown). The rAAV capsid and genome may trigger innate immunity via activation of Toll-like receptor 2 (TLR2) and TLR9, respectively. Activation of innate immunity can further promote adaptive immune responses. The capsid undergoes proteasomal degradation, and the resulting peptides are presented by major histocompatibility complex (MHC) class I molecules to CD8+ T cells. The CD8+ T cell can exert destructive cytotoxic effects to eliminate rAAV-transduced cells, resulting in the loss of transgene expression. The transgene product can elicit a humoral immune response to generate transgene product-specific antibodies that can compromise therapeutic efficacy. AAV, adeno-associated virus.
Following rAAV administration, the vector capsid triggers a robust humoral immune response to generate NAbs, preventing re-administration in most cases. For applications likely requiring repeated dosing, transient B cell depletion upon the first injection and induction of immune tolerance by rapamycin may be considered. In addition, the capsid can trigger a cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, which may lead to the clearance of transduced cells and therefore loss of transgene expression. This phenomenon appears prominent in humans and is not readily modelled in animals. It should be noted that the CTL response mounted against the rAAV capsid is much weaker than those mounted against other viral vectors such as adenoviral vectors. CTL response caused by rAAV administration may compromise therapeutic efficacy over time but generally does not pose a major safety concern. Some muscle-targeting clinical studies suggest that regulatory T (Treg) cells may play a role in restraining the effect of CD8+ CTLs. Pharmacological suppression of CD8+ T cells with steroids is effective in managing liver CTL response following systemic rAAV delivery and ensuring long-term transgene expression. Inspired by the induction of endogenous Treg cells in muscle-directed rAAV gene therapy and their potential role in limiting CTL response, administering autologous Treg cells as an adjuvant to in vivo gene transfer may provide a powerful approach for modulating rAAV immunity.
The transgene may encode a protein that is foreign to the host, as is the case for gene replacement therapies in patients with a null genotype or gene addition therapies with vectored antibody-like molecules. The transgene product may therefore trigger both B cell-mediated and T cell-mediated adaptive responses to generate transgene product-specific antibodies and CTLs. Circulating antibodies may prevent lasting therapeutic efficacy. Likewise, anti-antibody responses are currently a major barrier for developing AAV vectored antibodies for infectious diseases. The transgene product-specific CTL response was reported in muscle-targeted clinical trials in liver-directed haemophilia trials. Establishing the necessary enrolment criteria could have helped to mitigate such a risk. Importantly, the tolerogenic ability of the liver also impacts rAAV gene transfer. The transgene product-specific immune tolerance induced by liver-directed rAAV gene delivery is dose-dependent and likely involves Treg cells. This endogenous immune modulation phenomenon can be harnessed to achieve stable transgene expression and therapeutic efficacy.
In addition to eliciting adaptive responses, the rAAV capsid and vector genome are also sensed shortly after delivery by the innate immunity through Toll-like receptor 2 (TLR2) and TLR9, respectively. This response leads to the production of pro-inflammatory cytokines and promotes the adaptive response. Self-complementary rAAV genomes or vector genomes with high content were shown to further enhance the immune response. Therefore, preventing TLR signalling by depleting CpG dinucleotides in the rAAV genome has the potential to enhance rAAV-mediated gene expression. Another promising strategy is to incorporate a TLR9-inhibitory DNA sequence, such as multiple copies of TTAGGG derived from human telomeres, into the rAAV genome to evade innate immune surveillance. This approach was reported to reduce the immune responses associated with rAAV delivery in mice.
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