Newborn Screening, Cord Blood Banks, The Future Possibility for Cure?
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1 Newborn Screening, Cord Blood Banks, The Future Possibility for Cure? Anders Fasth Dept of Pediatrics University of Gothenburg, Gothenburg, Sweden And The Queen Silvia Children s Hospital, Gothenburg Newborn Screening for Severe PID 1
2 Why screening?!for severe PID SCID, some T cell deficiencies and thymus defects - prognosis is depended on early diagnosis!early diagnosis = before symptoms and signs have developed!rare disorders = SCID about 1.5 per newborns Transplanted before 3.5 months of age Severe Combined Immunodeficiency 95% Donor type matters 60% Transplanted after 3.5 months of age ESID Duke 2
3 SCID, severe T cell def and Thymus deficiencies! SCID more than 15 diseases! Severe T cell deficiencies how many?! Thymus deficiencies! DiGeorge (22q11 deficiency, CHARGE and others)! Nude SCID Common ground : Lack of T cells And how to screen?!number of lymphocytes or T cells!will miss at least 20% of severe T cell deficiency!needs fresh blood costly, logistics!trecs!can use Gutrie cards!automatic technique fast and cheap 3
4 T cell Receptor Excision Circles (TREC TRECs!Only expressed in T cells newly emerged from the thymus!circular pieces that do not replicate 4
5 The Wisconsin Program!"#$%&' ()2#"%' 341)2#"%' ()*+,'%)-"%' $.,/0-0"1' 5
6 Results from 2008! full term newborns!17 with low TREC!1 died of non-pid!1 refused!4 repeat TREC normal!11 had T cells counted (T, B, NK, naïve, memory T)! 2 had 22q11 deletion syndrome! 3 normal! 3 low T one DiGeorge, 1 RAC2 def, 2 idiopatic CD4 low Lessons learned!easy feasible test!no case of SCID missed!prematures born before week 37 problem!22q11 deletion syndrome screening can be done at the same time 6
7 Can also be applied to B cells!b cell receptor produced in the same way as T receptor!plus a second circular piece when switched from one immunoglobulin class to another!one heavy chain and two light chains (kappa and lambda)!methods to find B cells defects from Guthrie cards tested and works with KRECs Cord Blood Banking 7
8 !Why cord blood?!in homogenous populations still % no donor, for ethnic minorities 50%.!In third world and in multi-ethnic countries nobody knows how many will find a donor easily!establishment!how many units?!considerations on the ethnic mixture!costs!practicalities! About 14 millions volunteer donors in different registries! But the registries are in the rich part of the world not where the majority of the population is living 8
9 Why Consider Cord Blood?! In the average population of Caucasian origin about 20 % will not find a donor in the family or in a registry! For ethnic minorities 50 % or more might not find a donor! The less stringent need for HLA-matching Cord Blood Donors allows close to 100% to find a donor! In major part of the world with the ethnic mixture of each country it might prove difficult to find a donor in the registries placed mainly in Europe, North America, and Far East (Japan, Taiwan, China) HLA or Tissue Type HLA-F! HLA-A " " I! "616 alles! 6p21.3! Kromosom 6! HLA-E! HLA-C " " "440! HLA-B " " II I! "913! HLA-DRB1 " "368! HLA-DQA1 " II! " 7! DQB1 " " 48! Gives >1x different HLAcombinations 18 9
10 Why Less Risk For GvHD?!Other properties of cord blood stem cells?!other stem cells in cord blood that dampens the risk i.e. mesenchymal stem cells?!the mother fetus dyad with down regulated immune system?!the small cell dose = small number of T-cell too? 10
11 Advantages with Cord Blood (1)!Almost indefinite supply!no risk to the mother, nor to the child!ethnic balance can be achieved!less GvHD!Less viral contamination!plastic stem cells Advantages with Cord Blood (2)!Cord blood available at demand!no waiting for months as with unrelated volunteer donors!the frozen cells can be shipped world wide!you know what you have!do the stem cells last longer? 11
12 Disadvantages with Cord Blood!Limited number of stem cells!but you can use two units!limited number of stem cells and other cells!longer time to take!longer time to immune reconstitution!a possible risk to transmit rare inherited blood disorders!the logistics!collection and storage!costs What experiencies do we have of CBU in PID - world wide? Not much published hidden cases within other reports! Ongoing studies from CIBMTR!SCID 21 cord among 132 SCT for SCID!WAS 83 BM and 40 cord! Abstract from Duke at 2009 Tandem meeting!15 boys with WAS!BU/CY + FLU!5 were 5 or 6 out of 6 HLA antigen matched!10 were 4/6 matched!all engrafted!os 60% (median 89 mo, mo)!deaths: 3 infections, 1 GvH, 1 EBV lymphoprolif disorder 12
13 How many units do you need to freeze? 5 10 units per inhabitants! France today 0.91 units in 10 years 10 per inhabitants! USA 10 per in 10 years! Japan 10 per inhabitants today! Korea 10 per inhabitants today! Singapore 14 per inhabitants in 3 years! Sweden 1 per inhabitants today, in 3 years 5 per Concentrate on ethnic minorities!!increase the number of units collected from the minorities to at least 50%!Consider the ethnic mixture of your country!example Singapore! 3 major ethnic groups"! Collects in proportion to each of them " 13
14 Registry vs. Cord Blood Bank!Volunteers at a registry!mainly the educated middle class!minorities less likely to participate!cord Blood a waste product!easy to convince also the minorities to donate their newborn s cord blood!in Gothenburg we found the 97 % of the families were willing to donate Cell Dose matters Time to take and if take P=
15 Cell Dose Matters - thrombocytes P=<0.01 HLA Disparity between donor and patient can be compensated with more cells!hla compatibility >3 x 10 7 /Kg!1 antigen difference >4 x 10 7 /Kg!2 antigens difference >5 x 10 7 /Kg Cord blood is typed on antigenic level for A and B, and allelic for DR*B1 If possible chose disparity at A and/or B locus before DR*B1 15
16 Costs!In Europe and the USA the cost to prepare one unit is around 1,800 dollars!more than 50% is labor costs!collection, paper work, laboratory work!the cost to buy a unit from Cord Blood Banks are around dollars!with a bank in your own country!you can set your own price!!avoid a lot of the bureaucracy that follows with international request of a unit = increased speed Appropriate information - also in the language of the minorities Photo: Anna-Karin Larsson 16
17 More Than 20 Years With Cord Blood Transplantation What Have We Learnt?! 29 Oct 1988 first cord transplantation! (Editorial: You were just lucky nothing for the future)! UCB less immune reactive! Identified the least necessary cell dose! HLA-match - 4 of 6 antigens sufficient! UCB works also for adult! More than CB transplantations done world wide!the number increasing rapidly 2007 >2000 were done! Private banking not worth while and not cost-effective The Future 17
18 The Future!Neonatal screening!early Transplantation!Better technique!no or reduced conditioning!prognosis improved!cord Blood more often used!for the few with no donor Gene therapy!still not safe technique!better vectors safe and high integration 18
19 Gene therapy!problem!how to get the new non-mutated gene in place?!might insert into or close to another gene and disturb its function!how to get the new gene into the blood stem cell!do the new healthy cells have a survival advantage over the sick cells? Gene Therapy!5/20 children with X-SCID developed leukemia!0/20 children with ADA- SCID!3/3 with CGD malignant transformation!0/10 with WAS!Why the vector?!but ADA- SCID with old fashioned vector!was with new safer vector 19
20 Summary!Screening is feasible and can detect severe T cell deficiencies = better prognosis!cord blood offers a donor for almost everyone!gene therapy will come and maybe even replace transplantation (?) The End Thanks to!you my patients and their parents!nurses and doctors at The Queen Silvia Children s Hospital, Hematopoietic Stem cell Program 20
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