TY - JOUR
T1 - Progress, and prospects in the therapeutic armamentarium of persons with congenital hemophilia. Defining the place for liver-directed gene therapy
AU - Di Minno, G.
AU - Castaman, G.
AU - De Cristofaro, Raimondo
AU - Brunetti-Pierri, N.
AU - Pastore, L.
AU - Castaldo, G.
AU - Trama, Ugo
AU - Di Minno, M.
PY - 2023
Y1 - 2023
N2 - In persons with congenital severe hemophilia A (HA) living in high-income countries, twice weekly intravenous infusions of extended half-life (EHL) factor VIII (FVIII) products, or weekly/biweekly/monthly subcutaneous injections of emicizumab are the gold standard home treatments to grant days without hurdles and limitations. Once weekly/twice monthly infusions of EHL Factor IX (FIX) products achieve the same target in severe hemophilia B (HB). Gene therapy, which is likely to be licensed for clinical use within 1–2 years, embodies a shift beyond these standards. At an individual patient level, a single functional gene transfer leads to a > 10-yr almost full correction of the hemostatic defect in HB and to a sustained (3–6-yrs) expression of FVIII sufficient to discontinue exogenous clotting factor administrations. At the doses employed, the limited liver toxicity of systemically infused recombinant adeno-associated virus (rAAV) vectors is documented by long-term (12–15 yrs) follow-ups, and pre-existing high-titer neutralizing antibodies to the AAV5 vector are no longer an exclusion criterion for effective transgene expression with this vector. A safe durable treatment that converts a challenging illness to a phenotypically curable disease, allows persons to feel virtually free from the fears and the obligations of hemophilia for years/decades. Along with patient organizations and health care professionals, communicating to government authorities and reimbursement agencies the liberating potential of this substantial innovation, and disseminating across the Centers updated information on benefits and risks of this strategy, will align expectations of different stakeholders and establish the notion of a potentially lifelong cure of hemophilia.
AB - In persons with congenital severe hemophilia A (HA) living in high-income countries, twice weekly intravenous infusions of extended half-life (EHL) factor VIII (FVIII) products, or weekly/biweekly/monthly subcutaneous injections of emicizumab are the gold standard home treatments to grant days without hurdles and limitations. Once weekly/twice monthly infusions of EHL Factor IX (FIX) products achieve the same target in severe hemophilia B (HB). Gene therapy, which is likely to be licensed for clinical use within 1–2 years, embodies a shift beyond these standards. At an individual patient level, a single functional gene transfer leads to a > 10-yr almost full correction of the hemostatic defect in HB and to a sustained (3–6-yrs) expression of FVIII sufficient to discontinue exogenous clotting factor administrations. At the doses employed, the limited liver toxicity of systemically infused recombinant adeno-associated virus (rAAV) vectors is documented by long-term (12–15 yrs) follow-ups, and pre-existing high-titer neutralizing antibodies to the AAV5 vector are no longer an exclusion criterion for effective transgene expression with this vector. A safe durable treatment that converts a challenging illness to a phenotypically curable disease, allows persons to feel virtually free from the fears and the obligations of hemophilia for years/decades. Along with patient organizations and health care professionals, communicating to government authorities and reimbursement agencies the liberating potential of this substantial innovation, and disseminating across the Centers updated information on benefits and risks of this strategy, will align expectations of different stakeholders and establish the notion of a potentially lifelong cure of hemophilia.
KW - Benefits, theoretical risks
KW - Coagulation factor inhibitors
KW - Educational programs
KW - Extended half-life products
KW - Government bodies
KW - Reimbursement agencies
KW - Laboratory monitoring
KW - Non-substitutive therapies
KW - Patient organizations
KW - Prospective registries
KW - Quality of life
KW - Health care professionals
KW - Benefits, theoretical risks
KW - Coagulation factor inhibitors
KW - Educational programs
KW - Extended half-life products
KW - Government bodies
KW - Reimbursement agencies
KW - Laboratory monitoring
KW - Non-substitutive therapies
KW - Patient organizations
KW - Prospective registries
KW - Quality of life
KW - Health care professionals
UR - http://hdl.handle.net/10807/303913
U2 - 10.1016/j.blre.2022.101011
DO - 10.1016/j.blre.2022.101011
M3 - Article
SN - 0268-960X
VL - 58
SP - N/A-N/A
JO - Blood Reviews
JF - Blood Reviews
ER -