Analyses conducted in sheep fetuses have shown that treating hemophilia A prior to birth is safe, feasible, and immunologically beneficial, according to findings from a study published in the journal Nature Communications.
Individuals with severe hemophilia A have less than 1% of normal plasma concentrations of factor FVIII (FVIII) activity, thus experiencing life-threatening, spontaneous bleeds, such as connective tissue/muscle hematomas, internal bleeding, and hemarthroses that are associated with chronic, debilitating arthropathies.
Although improvements in treatments have advanced the standard of care among patients with severe hemophilia A, the burden of disease remains high, with joint disorders and the development of inhibitor antibodies reported in a considerable number of individuals within the initial 50 exposure days to FVIII. Thus, the prevention of breakthrough and life-threatening bleeding presents continuous challenges.
Rodriguez et al. noted that about 70% of individuals with hemophilia A have a family history of the condition, thereby permitting prenatal diagnosis and intervention. Prenatal therapies with the ability to provide FVIII levels that are curative or are sufficient to convert a life-threatening bleeding disease to a mild phenotype, while also inducing immune tolerance to the FVIII product, could have a key impact on the quality of life and life expectancy of patients with severe hemophilia A.
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In the current analysis, 25 sheep fetuses, at the human equivalent of 16 to 18 gestational weeks, were injected prenatally with human placenta-derived mesenchymal cells of 107/kg to 108/kg, which were bioengineered to generate an optimized FVIII protein.
Results of the study showed that these injections were associated with a considerable rise in plasma FVIII levels that persisted for over 3 years following treatment. In other words, prenatal transplantation of these FVIII/ET3-secreting cells was linked to increased levels of ET3 protein (ie, bioengineered human FVIII) for more than 3 years.
The researchers also reported the following findings:
- The sustained presence of the ET3 protein in the circulation is not associated with the induction of anti-ET3 immunoglobulin (Ig) M and IgG antibodies.
- There was an absence of ET3-specific memory T-helper 1 (Th1) and Th2 lymphocytes among recipients of in utero transplants.
- Human myeloid codon-optimized, bioengineered FVIII (PLC-mcoET3) cells are not immunologic and do not generate donor-specific cellular immune responses.
- PLC-mcoET3 does not induce anti-HLA class I and class II antibodies following in utero transplantation.
- Prenatal transplantation of PLC-mcoET3 is not associated with any hepatic or hematologic alterations.
- PLC-mcoET3 persists in the long-term in the engrafted tissues and upregulates certain tissue cell-specific transcripts.
“This study shows that within the samples analyzed, there were significant differences in levels of PLC-mcoET3 engraftment in the different organs and between animals,” the researchers explained. “Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating hemophilia A prior to birth,” they noted. “Of significance is that in utero transplantation with PLC-mcoET3 could eliminate the need for weekly dosing, while maintaining therapeutic levels that exceeded the new suggested clinical objective of >15% FVIII, which is intended to provide effective protection from the majority of spontaneous bleeds,” they concluded.
Rodriguez M, Trevisan B, Ramamurthy RM, et al. Transplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity. Nat Commun. Published online July 14, 2023. doi:10.1038/s41467-023-39986-1