1. Hematopoietic stem cell transplantation in inherited neurometabolic disease Mahshid Mehdizadeh MDAssociate professor of pediatric hematology and oncologyTaleghani stem cell transplantation centerShahid Beheshti medical university

2. An 11 years old male patient • His 8 years old brother had a progressive neurologic disease diagnosed as adrenoleukodystrophy • He had history of convulsion and some hearing loss During last months • Based on neurologic consultation his neurologic exam was normal except hearing loss

3. Lab and imaging results • EEG:Occasional sharp activities in a dysrythmic background • MRI:T2 abnormalities mostly in temporo occipital and brain stem • ABR:NL • VEP:NL • Cortisol:0.5 micro g/dl ( NL: 5-22) • ACTH:109 pg/ml • VLCFA: increasedC24,C26,C24/C22,C26/C22 typical for ALD

4. He was full compatible with his 13 years old brother • His brother was also evaluated by MRI, cortisol level, VLCFA all in normal values • Patient was completely evaluated for infectious disease and underwent necessary examinations and tests for BMT(heart, lung ,ENT ,dentistry ,genetic ,..) • Just before transplantation he also had some degrees of visual impairment • He was planned for a myeloabelative conditioning • During transplantation he experienced several episodes of seizures and rise of LFT up to10 times and some degrees of encephalopathy and febrile neutropenia • patient engrafted successfully • Now his neurologic problems are stable and somehow improved but his cognitive state has not improved yet

5. Lysosomal Storage Disorders • Inherited metaboloc disorders are a diverse group of diseases arising from genetic defect in lysosomal enzymes or peroxisomal function • Devasting systemic processes affecting neurologic and cognitive function. Early death is a common outcome.

6. Sandoff 2% Gaucher 14% Gm1 Gangliosidosis 2% Mucolipidosis II/III 2% Niemann Pick A/B 3% MPS I H/S 9% Maroteaux-Lamy 3% Niemann Pick C 4% Sanfilippo B 4% Metachromatic Leukodystrophy 8% Tay-Sachs 4% Cystinosis 4% Sanfilippo A 7% Morquio 5% Fabry 7% Pompe 5% Krabbe 5% Hunter 6% (For Australia1980-1996; Meikle et al., JAMA 281;249-254 Lysosomal Storage Disorders MPS 34%

7. Early diagnosis/Early transplantation • Timely diagnosis and immediate referral for available treatments such as hematopoietic stem cell transplantation(HSCT) are essential steps in management • Allogenic HSCT for IMD is performed using infusion of donor stem cells after immunosuppression and myelosuppression with a chemotherapeutic regimen

8. How HSCT could correct an IMD • Cross –correction of metabolic defects with transferable lysosomal enzymes(direct transfer of enzyme from adjacent cell or mannose 6phosphate receptor endocytosis) • Immunosuppression and decrease in perivascular inflammation in x-ALD • Migration and growth of donor cells in liver (Kupffer cells),lungs(alveolar macrophages) and CNS microglia

9. Indications for HSCT • Hurler(MPS IH) • Hurler/Scheie(MPS IH/S • Scheie(MPS IS) • Hunter severe (MPS IIA) • Hunter attenuated(MPS IIB) • Sanfilippo(MPS III A/B/C/D) • Maroteaux-Lamy(MPS VI) • Sly(MPS VII) • Standard therapy • Optional • Optional • Investigational • Investigational • Investigational • Investigational • Investigational Disease:MPS HSCT

10. Hurler syndrome • The most severe form of MPS due to accomulation of glycosaminoglycan • More than 500 HSCT scince 1980 • HSCT is effective treatment but must be performed early

11. Hurler syndrome • What is stem cell source? Normal HLA match sibling/unrelated cord blood • What is the conditioning regimen?standard BU/CY[EBMT 2005 guidline,eurocord-Duke university] • How is survival after HSCT? 91%(4years) • What is the role of enzyme replacement therapy?

12. Hurler syndrome • How is post transplant outcome?reduction of obstructive airway symptoms and hepatosplenomegaly, improvement of cardiovascular function,hearing ,vision,growth,hydrocephalus but not pretransplant cerebral damage

13. Other MPS syndromes and HSCT • Hunter [MPS II] :8 boys successful HSCT French study/ ERT • Sanphilipo[MPS III]: ERT is not available, HSCT data is not adequate 19 children in Duke university but only effective in two <2 years old children • Marotexlamy[MPS VI]: Limited data,an option in patient who failed to ERT

14. Indications for HSCT • X linked ALD • MLD:early onset • MLD:late onset • GLD:early onset • GLD:late onset • Standard therapy • Unknown • Standard therapy • Standard therapy • Optional Leukodystrophies HSCT

15. Adrenoleukodystrophy • A rare, inherited disorder • Was first described in Germany in 1923 • Overall frequency : 1:17000 • Nervous system ,Adrenal gland, Testes' Leyding cells • The most common form is an X-linked condition : • Defect in the gene ABCD1 & Accumulation of VLCFAs (C26:0) JAMA, 2005.Vol 294:3131-34

16. X-ALD Degradation of fatty acids with less than 20 carbons occurs in mitochondria, above 20 carbons in peroxisomes. The defective gene in X-ALD encodes for the ABCD1 protein, a peroxisomal half transporter that requires homodimerization or heterodimerization with other members of the ABCD1 family Drug Discovery Today: Therapeutics Strategies.2008.vol 5 :237-242

17. Organ involvement in X-ALDIn both organs it leads to accumulation of very long chain fatty acids,as demonstrated by lipid spicules and crystallization in tissue Drug Discovery Today: Therapeutics Strategies.2008.vol 5 :237-242

18. PHENOTYPES • 4 major phenotypes of ALD • Cerebral ALD (CERALD) • Adrenomyeloneuropathy (AMN) • Addison disease • Asymptomatic status Arch Neurol.2005.62:1073-1080

19. JAMA, 2005.Vol 294:3131-34 , www.UpToDate.com

20. JAMA, 2005.Vol 294:3131-34 , www.UpToDate.com

21. THERAPEUTIC APPROACHS • Pharmacological Treatment Strategies : • Treatment of Adrenal & Gonadal Insufficiency • Lorenzo's Oil • Immunomodulators & Immunosuppresive Drugs • Statins • Pharmacological Induction of The Redundant Gene ABCD2 • Antioxidant • Hematopoietic Stem Cell Transplantation (HSCT) • Gene Therapy ,Brain Pathology 2010.vol 20: 845–856

22. HEMATOPOIETIC STEM CELL TRANSPLANTATION • The first report about a favorable effect of HCT in CERALD was published in 1990 • The treatment of choice for individuals with early stages of CERALD • For asymptomatic patients with normal MRI is not recommended • For patients with AMN without cerebral involvement is not recommended • In AMN with early cerebral involvement & adult CERALD, experiences with HCT is very rare • Visual dysfunction may continue to progress in patients after HCT • prognostic factors predictive of vision loss : • MRI score >11, PIQ < 76, parieto-occipital demyelination on MRI JAMA, 2005.Vol 294:3131-34 ,.Brain Nerve 2007 59(4):339-46 ,Journal of AAPOS 2008.vol 12 :273-276 Expert Reviews Neurotherapy.2008.vol 8:1367-79,Brain Pathology .2010.vol 20: 857–862

23. ALD and HSC transplant • What is the scoring system?32 point MRI scale and neurologic score based on the number of neurological deficits • How is the lab test after HSCT?Elevated VLCFA and adrenal insufficiency will continued • Will the Lorenzo oil effective after HSCT? May be before transplant not after

24. Globoid leukodystrophy “Krabbe disease” • Caussed by deficiency of galactocerebrosidase • Spasity,mentalretardation,blindness,deafness ,sizure and early death are natural history of the disease • Prenatal diagnosis is possible by gene defect 14q31 • HSCT is the only available therapy

25. Globoid leukodystrophy “Krabbe disease” • First report in 1998 by Krivit in 5 late onset affected boy who responded to HSCT • Report of successful neonatal cord blood transplantation in 25 neonates by • Escolar in 2005 but transplantation in • symptomatic infants are less effective

26. Metachromicleukodystrophy • A lysosoma disorder due to deficiency of Arylsulfatase A and increased urinary sulfatides(very important to rule out psudodeficiency) • Clinical phenotypes:early infantile,late infantile,early juvenile,late juvenile,adult form • The first report of HSCT about 20 years ago and more than 100 transplantation later but long term data are not available

27. Metachromicleukodystrophy • Usually children who were transplanted for symptomatic or asymptomatic late infantile MLD perfoemed poorly in all aspects • In late onset juvenile MLD and adult forms ,CNS disease was stabilized after HSCT • Current preferred practice is to transplant only presymptomatic or minimally affected chidren

28. HSCT is not effective • Alexander syndrome • Morquio syndrome • Vanishing white matter disease • Zellweger syndrome • Fabry disease Canavan syndrome • Cystinosis • Cebrotendinous xanthomatosis • Tay sachs/Sandhoff /GM1 Gangliodosis

29. HSCT experimental reports • Woman disease • Alpha-Manosidosis • Neiman –pick type B/C2 • Nonneuropathic Gaucher disease (type 1)

30. New directions • Stem cell gene therapy • Usage of mesenchymal stromal cell as vector

34. Thank you