OC 50.1 - Transplantation of fetal liver and adult bone marrow cells for phenotypic correction of hemophilia A.

Tuesday, July 12, 2022

10:45 AM – 11:00 AM

Location: ExCel Center, ICC Auditorium

Presentation Format: In-Person

Presenting Author(s)

Saicharan Akula

PhD student
universita del piemonte orientale
Novara, Piemonte, Italy

Co-Author(s)

Sm

Simone merlin

Assistant professor
universita del piemonte orientale
novara, Piemonte, Italy
AC

Alessia Cottonaro

PhD student
universita del piemonte orientale
Novara, Piemonte, Italy
Antonia Follenzi, MD, PhD

Full professor
Department of Health Sciences, University of Piemonte Orientale, Novara, Italy
Novara, Piemonte, Italy
Ms

Maria Jose sanchez

professor
Centro Andaluz de Biología del Desarrollo (CABD)
madrid, Madrid, Spain
eb

ester borroni

Assistant professor
universita del piemonte orientale
novara, Piemonte, Italy
vK

vakhtang Kalandadze

PhD student
universita del piemonte orientale
novara, Piemonte, Italy
Tg

Tamara garcia leal

Technician
Centro Andaluz de Biología del Desarrollo (CABD)
madrid, Madrid, Spain
LS

Luis J. Serrano ramos

post doc
Complutense University of Madrid
madrid, Madrid, Spain
al

antonio liras

professor
Complutense University of Madrid
madrid, Madrid, Spain
sb

silvia buzzi

Technician
universita del piemonte orientale
Novara, Piemonte, Italy

Background: We previously showed that adult-derived FVIII-producing cells, i.e. liver sinusoidal endothelial cells (LSECs) and hematopoietic stem cells (HSCs), can be used for the treatment of adult HA mice. However, after transplantation in busulfan-conditioned newborn mice, adult LSEC/HSC cannot efficiently engraft compared to murine fetal liver (FL) hemato/vascular cells from day 11-13 of gestation (E11-E13) that strongly reconstitute the hematopoietic compartment and showed multi-organ endothelial reconstitution potential and FVIII secretion ability.

Aims: To investigate the ability of FL cells in repopulating the hemato/vascular compartment following transplantation in newborn HA mice without preconditioning.

Methods: We transplanted adult BM or FLE11-E13 cells from GFP mice into newborn and adult HA mice pre-treated (+BU) or not (noBU) with busulfan. The engraftment level and FVIII activity was assessed starting from 4w after transplantation and followed-up for 18m. Bleeding phenotype correction was verified by hemarthrosis induction and bleeding assay.

Results: In all BU-conditioned groups we observed long term (18m) stable GFP+ blood engraftment (>60%) with up to 16% FVIII activity following FL and BM cells transplantation. Interestingly, without pre-conditioning we observed lower but stable engraftment (≤12%) and consequent FVIII activity (1-4%) after FL cells transfer, while BM cells did not engraft in noBU mice. Tail bleed challenge and induced hemarthrosis experiments further confirmed the phenotypic correction in all mice receiving FL/BM+BU and in FLnoBU mice. Additionally, we observed an increased survival rate in corrected mice (80%) compared to HA controls (30%). None of the transplanted mice developed anti-FVIII or anti-GFP antibodies.

Conclusion(s): Transplantation of HSCs from adult BM and FL may provide a novel, more stable and highly promising preclinical model for pediatric HA treatment. Our results show FL cells having higher engraftment ability, thus paving the way for studies aimed at maximizing the engraftment and proliferation of donor FVIII-corrective cells while minimizing/avoiding harming pre-conditioning regimens.