Reply

Abstract

We appreciate the questions raised by Thanh et al about our clinical trial evaluating the safety and efficacy of intravenous umbilical cord blood infusion for the treatment of children with autism spectrum disorder (ASD). We did not target CD34 dosing in this clinical trial because our preclinical studies and early-phase clinical trial data in children with ASD and children with cerebral palsy (CP) did not show any association between improvement and CD34 dosing. Our data showed that the cell responsible for modulation of neuroinflammation, stimulation of oligodendrocyte proliferation, remyelination, and increasing whole brain connectivity is the CD14+ monocyte in cord blood.1Saha A. Buntz S. Scotland P. Xu L. Noeldner P. Patel S. et al.A cord blood monocyte-derived cell therapy product accelerates brain remyelination.JCI Insight. 2016; 1: e86667Crossref PubMed Google Scholar, 2Scotland P. Buntz S. Noeldner P. Saha A. Gentry T. Kurtzberg J. et al.Gene products promoting remyelination are up-regulated in a cell therapy product manufactured from banked human cord blood.Cytotherapy. 2017; 19: 771-782Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 3Carpenter K.L.H. Major S. Tallman C. Chen L.W. Franz L. Sun J. et al.White matter tract changes associated with clinical improvement in an open-label trial assessing autologous umbilical cord blood for treatment of young children with autism.Stem Cells Transl Med. 2019; 8: 138-147Crossref PubMed Scopus (18) Google Scholar, 4Saha A. Patel S. Xu L. Scotland P. Schwartzman J. Filiano A.J. et al.Human umbilical cord blood monocytes, but not adult blood monocytes, rescue brain cells from hypoxic-ischemic injury: mechanistic and therapeutic implications.PLoS One. 2019; 14: e0218906Crossref PubMed Scopus (8) Google Scholar Cord blood banks do not measure CD14 cell content but do measure total nucleated cells (TNCCs) and CD34. For this reason, selection of cord blood units for the participants with ASD and CP in our clinical trials has been based on TNCC. We are investigating whether infused CD14 cell doses correlate with response but do not have that data at this time. In our first randomized trial using autologous cord blood in young children with CP, we reported an effective dose threshold of 25 million cells/kg.5Sun J.M. Song A.W. Case L.E. Mikati M.A. Gustafson K.E. Simmons R. et al.Effect of autologous cord blood infusion on motor function and brain connectivity in young children with cerebral palsy: a randomized, placebo-controlled trial.Stem Cells Transl Med. 2017; 6: 2071-2078Crossref PubMed Scopus (57) Google Scholar We saw the same trend in our initial phase I trial in children with ASD.6Dawson G. Sun J.M. Davlantis K.S. Murias M. Franz L. Troy J. et al.Autologous cord blood infusions are safe and feasible in young children with autism spectrum disorder: results of a single-center phase I open-label trial.Stem Cells Transl Med. 2017; 6: 1332-1339Crossref PubMed Scopus (66) Google Scholar Since that time, we have targeted greater TNCC doses in our trials involving children with CP and have observed a dose effect up to 100 million cells/kg (unpublished data). For our trials with children with ASD, we target a minimal dose of 25 million cells/kg. Although CD34 cell dosing is quantitated in all our trials, we have not seen any relationship between CD34 dose and response. The CD34 doses in the trial reported in The Journal are typical of CD34 doses achievable with an unmodified cord blood transplant or cord blood infusion. We are following children in the trial published in The Journal for a period of 12 months postinfusion and will be reporting the 12-month outcome data at a later date. A phase II randomized clinical trial of the safety and efficacy of intravenous umbilical cord blood infusion for treatment of children with autism spectrum disorderThe Journal of PediatricsVol. 230PreviewDawson et al have drawn attention to the outcomes of umbilical cord blood (UCB) administration for the treatment of 180 children with autism spectrum disorder (ASD).1 Because there is a substantial interest in stem cell therapy as a potential candidate or therapeutic approach for ASD, these outcomes are noteworthy. The authors provide findings from a large sample size, randomized process with a control group, and processing paradigms, although the results did not support the efficacy of UCB administration. Full-Text PDF