Prenatal Therapy with Placental Cells Transduced with an Engineered fVIII Transgene Results in Curative fVIII Plasma Levels for 3 Years after Birth, Without Immune- or Toxicity-related Adverse Events

M. Rodriguez¹, B. Trevisan¹, s. george¹, R. Ramamurthy¹, J. Shields², D. Schwahn³, J. Figueroa⁴, D. Meares⁴, J. Owen⁴, M. Gautreaux⁴, A. Atala¹, C. Doering², HT. Spencer², C. Porada¹, G. Almeida-Porada¹

¹Wake Forest Institute for Regenerative Medicine, Winston Salem, United States, ²Emory University, Atlanta, United States, ³Zoetis Veterinary Medical Research and Development, Kalamazoo, United States, ⁴Wake Forest School of Medicine, Winston Salem, United States

Abstract Number: OC 75.1

Meeting: ISTH 2021 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia Gene Therapy

Background: Treating hemophilia A (HA) prior to birth is a feasible, yet unexplored clinical approach that, even if not curative, could convert a severe to a mild phenotype and induce tolerance to FVIII, eliminating the risk of inhibitors.

Aims: To determine whether prenatal therapy (PNT) using human placental cells (PLC) transduced with a lentiviral vector encoding a bioengineered fVIII transgene (mcoET3) leads to increased fVIII activity in plasma, without eliciting an immune response.

Methods: Ultrasound-guided PNT was performed in sheep fetuses (n=23) at 60-64 gestational days. To determine whether treated animals developed an immune response to mcoET3, ELISAs were performed at 3-6 and 10-16 months postnatally, and ELISpot assays for IFN-g (Th₁) and IL-4 (Th₂) were performed at 3 different time points after birth. To investigate if the PNT recipients developed an immune response to the cells, one-way mixed lymphocyte reactions (MLR) and detection of anti-HLA antibodies using a screening panel-reactive antibody test (PRA) were performed.

Results: PNT animals followed over a 1-year (n=14), 2-year (n=9), and 3-year (n=6) period had increased mean plasma fVIII activity levels of 57%, 42%, and 35%, respectively. PNT recipients were devoid of anti-mcoET3 IgG, and no mcoET3-specific Th₁ or Th₂ cells were ever detected in any of the PNT recipients. MLR demonstrated robust reactivity towards third-party human lymphocytes, but not to the transplanted PLC. In addition, no PLC-specific anti-HLA antibodies were found, however 2 of the treated animals had detectable naturally-occurring xenogeneic antibodies.

Conclusions: PNT of fetal sheep recipients resulted in sustained high fVIII plasma levels for more than 3 years after birth, with no evidence of therapy-related toxicity, nor the development of anti-fVIII antibodies. Thus, these studies attest to the feasibility, immunologic advantage, and safety of treating HA prior to birth.

To cite this abstract in AMA style:

Rodriguez M, Trevisan B, george s, Ramamurthy R, Shields J, Schwahn D, Figueroa J, Meares D, Owen J, Gautreaux M, Atala A, Doering C, Spencer H, Porada C, Almeida-Porada G. Prenatal Therapy with Placental Cells Transduced with an Engineered fVIII Transgene Results in Curative fVIII Plasma Levels for 3 Years after Birth, Without Immune- or Toxicity-related Adverse Events [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/prenatal-therapy-with-placental-cells-transduced-with-an-engineered-fviii-transgene-results-in-curative-fviii-plasma-levels-for-3-years-after-birth-without-immune-or-toxicity-related-adverse-events/. Accessed September 29, 2023.

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