Thomas J. Langan, M.D. Department of Neurology State University of NY at Buffalo

Transcription

1 Enhancement of Newborn Screening to Improve the Efficacy of Cord Blood Transplant for Krabbe Disease Thomas J. Langan, M.D. Department of Neurology State University of NY at Buffalo

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3 0RIG INALARTICLE Transplantation of Umbilical-Cord Blood in Babies with It1far1tile Krabbe~s Disease Maria L. Esc alar, M.ID., MicheleD. Poe, Ph.D.: James M. Provenzale: M.., Karen C. Rrehards] M.D., June All"son. R.N., Susan Wood= P.N.P. 1 David A. Wenger] Ph.D., Dan el Pietryga, M.D., Donna Wall 1 M.D. 1 ~ artin Champagne ~ M.D. ~ Richard orse, ~.0., ~NiJUam Krivit, M.D., Ph.D.; and Joanne Kurtzberg, 1.0. NEngIJ ed 20 5: 352: May 19, 2005 DOl: /NEJ 1Da0 2604

4 Kaplan Meier Estimates of the Probability of Overall Survival among Patients with Krabbe's Disease. As)mp omattc ne wborns 0.4 S} mptoma. c nfants 0.2 ~.. ~-+- r Untreated control group '-~\,...., ; ;..~ ; i! ,,--,.----,--.---,--,---,r !2 24 l6 c;o A!re (months) 108 Escolar ML et al. N Engl J Med 2005;352:

5 Long Term Follow-up of Transplanted Early Infantile Krabbe Patients (Neurol. 89: , 2017)

6 Cognitive Development After Presmyptomatic Transplantation

7 Motor Development after Transplantation

8 Survey of Living Krabbe Patients from Buffalo Registry- Objectives 1. Develop a new Quality of Life (QOL) survey to better describe the natural history, phenotypes and responses to stem cell transplantation (SCT) of Krabbe Disease (KD). 2. Assess the concurrent validity and reliability of this survey, the Leukodystrophy QOL Assessment (LQLA), by co-administering it with the Vineland, an already validated QOL survey.

9 METHODS Phone calls to living patients in WWR. N= 33 ( of 45 attempted) 11 Early Infantile KD (EIKD), 7 Late Infantile KD (LIKD), 12 late onset KD (LOKD), and 3 with genotypes indicating risk for LOKD. SCT was achieved in cases of EIKD (2 before and 2 after symptoms emerged), LIKD (1 after symptoms) and LOKD ( 3 before and 3 after symptoms).

10 Measure Quality of Life Survey: Differences Between Transplant Groups Sample of Krabbe Cases N = 30 Estimated Mean by Transplant Time Transplant ANOVA P-Value None (N = 19) Post-Symptom (N = 6) Pre-Symptom (N = 5) Overall , 2 Communication , 2 Daily Living , 2 Social , 2 Motor , 2 Duncan Grouping 1 Indicates pre-symptomatic transplant mean significantly higher than no-transplant mean 2 Indicates pre-symptomatic transplant mean significantly higher than post-symptomatic transplant mean

11 Quality of Life Survey: Phenotypic Differences Sample of Krabbe Cases N = 30 Measure Phenotype Estimated Mean by Phenotype Duncan ANOVA P- EIKD (N = 11) LIKD (N = 7) LO (N = 12) Grouping Value Overall Communication , 2 Daily Living Social Motor , 2 1 Indicates LO mean significantly higher than EIKD mean 2 Indicates LO mean significantly higher than LIKD mean 3 Indicates no significant differences between group means

12 Presymptomatic/Early Transplantation for Krabbe Disease 1. It results in significant improvement of survival, cognitive function and quality of life. 2. Survey of quality of life better defines early infantile Krabbe (speech and communication deficits predominantly distinguish phenotypes ). 2. The benefits upon cognitive function and quality of life are not observed after post-symptomatic transplantation. 3. Consequently, early diagnosis of risk for Krabbe after NBS will enhance the efficacy stem cell transplantation.

13 Psychosine Hypothesis It postulated that galactosylsphingosine (psychosine), which cannot be degraded due to the underlying genetic defect, is responsible for the very rapid loss of the oligodendrocytes and the consequent paradoxical analytical finding, the lack of accumulation of the primary substrate, galactosylceramide, in patients' brain. It took nearly ten years before the actual accumulation of psychosine was demonstrated in human Krabbe patients and also in the brain of twitcher mice, an equivalent murine mutant. From K. Suzuki, J. Neurochem Res Mar;23(3):251-9.

14 .. G lactosyl _phingo ine G 1acto ylcer nlide CJ (Psychosine),/:, H f3-9alactocerebrosidase!l Q. (Krabbe.. 0 disease).,t:, c. Q» c acid ceramidase acid sphingonlyelinase 0 phingo in~ Ceramide 0') (Farber di ease) (Niemann-Pick disease Sphingomyelin c:: -.&:. type A and B) P glucosidase (Gaucher disease) a.. (I) ll l!! ~ Glucosylsphingosine (Giucopsycho ine) Gfucosylceranlide Ly o

15 1 hthcrit lt. fcmb n 4:201. -) J 8: ~ LO. L007/s L LS-98:22-:z. ORIGINA.\l,M{11CLE lea 1rement of p,.. cho in in dried blood pot ~a po, ible impro. ement tone rbo n. creenin~ rogram. for Krabbe di. ea ~e ~Coleo1an T. Tm:geon.. Joseph J ~ Or:s In i.. Ka11en A. n den.. t\tark..1. t\1 a em.. Thoma J'"' angan tar'"~ L"' [sc,oli~r.. Patrida Duffner.. De In 0 I bee.. llimi tar ~BJvrilo.... il\l, 111:iortoreIIi.. Pi!i!rO Rin ajdo.. K imi... o Ra... n1ond.. Dj!i!hiLh I uern

16 EICLO 50D JWD 30.0 : r to.o -...J ao -: r ~ -r: B P-0..~ :::::: a.. E "-0 C:.].. - a:: J "10... ' >... _._ (!"] 2.D..:L.-.. t.o _L Fl r [.~ _L E ~ Ill.. P...ru=685 P-o.lr."SQ P-0. DB6 o.e (12 p...o_(j343 C~::J p.o:fj. 00)1 Pd:UDII1 0.1 lj, A IB c 0 IE F G H y No:rmal [:()Otro a J.. v I ll '{' J "-..,

17 J ournal of euroscience Reserdrch 94: (...016) Can Psychosine and Galactocerebrosidase Activity Predict Early-Infantile Krabbe's Disease Presymptomatically? 1.2 T- 11.1_ 2 3 K ll_'"' 1 I 1 ] 2 1 I J 0.. "' 4 R and.. L. C ar-ter~ LLil-'\ITrencc raluetz~ aluii" a a ~ oscp 1.. rsnm~ Arrty L. Barczyko ;vslci~ 1 1 Diettich Matern, 5 and hontas J. Langmn 2 "" 1 *

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19 7.5 Bivariate Normal Limits Estimated from Wadsworth Normative Sample (N = 166) Univariate Standardization of Natural Log of Psychosinc/GALC 5.0,.-.-. >-< 2.5 r:/) ~ '-._/ 3 C1) " 0.0 N 1-. "ro " c:... ro -2.5 r:/) Standardized LN(GALC) D % Prediction Ellipse % Prediction Ellipse 99% Prediction Ellipse 95% Prediction Ellipse 50% Prediction Ellipse Nonnal Wadsworth Observations Standardized using means and standard de\iations estimated from a sample of nonual newboms with measurements from \Vadswortl1 lab in 2016(LN(GALC): Mean = 0.67, SD = 0.90; LN(PSY): Mean = -1.00, SD = 0.51)

20 Bivariate Normal Limits Estimated from Wadsworth Normative Sample (N = 166) Univariate Standardization of Natural Log ofpsychosine/galc With Group H (N = 8): EIKD Asymptomatic Cases (NBS) * Standardized LN(GALC) D % Prediction Ellipse D 99.99% Prediction Ellipse 99% Prediction Ellipse 95% Prediction Ellipse 50% Prediction Ellipse Normal Wadsworth Observations + Group H Observations Standardized using means and standard deviations eslimated from a sample of nonnal newborns with measurements from Wadswotth lab in 2016(LN(GALC): Mean = SO = 0.90; LN(PSY): Mean = -1.00, SO = 0.51) +Standardized using nonnative distribution estimated from Wadswotth!Mayo data*(ln(galc): Mean = 1.24, SO = 0.58: LN(PSY): Mean= 0.88, SO= 0.41) *See Carteret. al., 2016 JNR.

21 Bivariate Normltl Limits Estimated from Wadsworth Normative Sample (N = 166) Univariate Standardization of Natural Log ofpsychosine/galc With Group D (N =8): GALC M utation Carriers (NBS) ,.-... :>-< r:/1 p '"-" 3 '"0 (!) 0.0 -~ '"0 a '" r:/ Standardized LN(GALC) D % Prediction Ellipse D 99.99% Prediction Ellipse 99% Prediction Ellipse 95% Prediction Ellipse 50% Prediction Ellipse Normal Wadsworth Observations + Group D Observations Standardized using means and standard deviations estimated from a sample ofnormal newborns with measurements from Wadsworth lab in 2016(LN(GALC): Mean = 0.67, SD = 0.90; L (PSY): Mean = -1.00, SD = 0.5 1) +Standardized using norutative distribution estimated from Wadsworth/M.ayo data*(ln(galc): Mean = 1.24, SD = 0.58; LN(PSY): Mean = 0.88, SD = 0.41) *See Carter et. al., 2016 JNR

22 Analysis of Dried Blood Spots to Develop The BVNL Krabbe NBS Tool 1. The data set consisted of: a. 15 newborn blood spots of known Krabbe patients collected by the Buffalo Research Group. b. 8 newborn blood spots from high risk cases followed in NY State. c. 3 blood spots from 3 late infantile ( 6-48 month onset) Krabbe patients followed at UPMC obtained soon after symptoms emerged. d. 1 blood spot obtained from a UPMC patient after treatment. 2. Assays of Psychosine and Galactocerebrosidase performed at Wadsworth Laboratories, NY State Department of Health.

23 Pre-symptomatic or High Risk? Pre-symptomatic cases are defined as having low enzyme levels and predictive genotypes( e.g,. 30 kb deletion homozygous or compound heterozygous with known high risk alleles). These include siblings of known cases. High risk cases have low enzyme consistent with Krabbe, but nonpredictive genotypes ( e.g, 30 kb heterozygotes with non-pathogenic additional allele 2 of 8 cases). These include possible late onset alleles and VOUS. (6 of 8 cases). All remained free of symptoms for 2-3 years.

24 BVNL Results from Krabbe Bloodspots

25 BVNL Results from 8 Asymptomatic, High Risk NY Cases

26 Bloodspot BVNL Summary Every infant whose newborn blood spot BVNL result was in the high risk zone on the probability ellipse was destined to develop Krabbe disease in infancy or early childhood. None of the New York State high risk infants newborn bloodspot results fell within the high risk zone of the ellipse, even though 5 of 8 had PSY values that would prompt concern. 1 transplanted patient whose blood spot was obtained after treatment had a normal BVNL result.

27 Accuracy of BVNL for Krabbe Prediction

28 Advantages of BVNL Tool for Predicting Krabbe Symptoms Soon After a Positive Newborn Screen 1. The false positive rate can be controlled for example at 10-6 ; this means that if all 4 million newborns in US were screened for Krabbe each year, no more than about 1 false positive very 2.5 years. 2. The Positive Predictive Value is 98.5 %. 3. This dramatic reduction of the false positive rate should facilitate early diagnosis and enhance the efficacy of treatment.

29 BVNL Advantages 4. Costly and painful diagnostic tests- LP, MRI, NCVSmay eventually be unnecessary. 5. BVNL calculations can be performed readily on open access, inexpensive software (e.g. R program). 6. There is no need to share any patient profiles or other reference data.

30 Issues Identified by Evidence Review EIKD, The Condition: need consensus about the case definition of what constitutes Early Infantile Krabbe Disease (EIKD) Test for EIKD, Screening and Diagnosis: there is a need for additional information about the testing algorithm for EIKD. It is important to ascertain whether testing for Krabbe disease would be a stand alone test or done with multiplex testing, in part because of the cost implications Treatment for EIKD: More information is needed about the specific benefits of Hematopoietic Stem Cell Transplant (HSCT) to treat patients and what mutations would benefit most from HSCT *Text taken directly from NBSTRN.org/resources/gaps-in-research

31 Progress in Filling Krabbe Disease Gaps of Knowledge EIKD, the condition: Our recent study of natural history and long term QOL better defines phenotypic expression. Test for EIKD, screening and diagnosis: The BVNL tool is potentially an extremely accurate tool for early diagnosis, essentially eliminating false positives, and enhancing treatment outcomes. Treatment for EIKD : Benefits of pre-symptomatic transplant upon survival, cognition and QOL have recently been established.

32 Filling the gaps in knowledge about Krabbe treatment, diagnosis and phenotypes

33 Acknowledgements NYS Dept. of Health: Mayo Clinic: Duke Univ.: J.Orsini D.Matern J. Kurtzberg D.Kay C.Turgeon H. Immelt M. Caggana Univ. of Pittsburgh: Mt. Sinai: M.Escolar M. Wasserstein M.Poe P. Levy SUNY Buffalo R.Carter, A. Barczykowski, K. Jalal, L. Wrabetz, L. Feltri Funding: R-21 HD (TJL, RC, LW, AB, KJ) LDN-U54NS (TJL)