current ald therapeutic options

7/31/2019 Current ALD Therapeutic Options

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Current ALD therapeut ic opt ions

I t i s impor t an t t o unde r s t and a t t he ou t se t t h a t t he r e i s p r e sen t l y no comp le t e cu r a t i v e t he r apy fo r X-ALD.

A va r i e t y o f s y mptoma t i c the ra peu t i c t r e a tmen t s f or a f fe c t edind iv idua l s a r e p r e sen t howeve r . Men w i th AMN and symptomat i c

w ome n ca r r i e r s w i l l o f t e n bene f i t f r om phys io the r apy and age nt stha t add r e s s :

Spas t i c i t y Neur opa th i c p a in Bladde r d i s r up t ion

Boys and men w i th ce r eb r a l d i s ea se w i l l r equ i r e mon i to r ing o f nu t r i t i on and when app r op r i a t e a g a s t r o s tomy tube . The i r func t ionmay de t e r io r a t e qu i ck l y and the r e a r e o f t en s eve r e and pa in fu lmusc l e spa sms a s soc i a t ed w i th p r og r e s s ion . Th i s w i l l r equ i r e

an t i spa smod i c med i ca t i ons ( such a s d i cyc lomine and hyoscyamine )and Ana l ge s i a . F am i l i e s w i l l o f t en bene f i t f r om pa l l i a t i v e c a r ese r v i ce s t oo .

A dre na l rep lace ment

A drena l ho rmon e the rapy i s manda to ry a nd l i f e sa v ing fo r pa t i e n t sw i th ad re na l i n s u f f i c i e ncy . I nd iv idua l s a nd the i r f am i l i e s s hou ldr ece i ve p r ope r i n s t r uc t i on and managemen t o f ad r ena l r ep l acemen t ,r equ i r emen t s fo r med i ca l a l e r t b r ace l e t s , and the r ecogn i t i on and

r ap id t r e a tmen t o f impend ing c r i s i s . Unfo r tuna t e l y , ad r ena lr ep l acemen t does no t a l t e r neu r o log i c p r og r e s s ion .

(Add i t i ona l i n fo :h t tp ://mar r ow .o r g/P a t i en t/Di sea se_and_Tr ea tmen t/Abou t_Your _ D i sea se/Met abo l i c_Di so r de r s/Cer eb r a l_X-L inked_ALD.aspx#Hor moneRep l acemen tTher apy )

H ematopo ie t i c s t em ce l l t r ansp lan t

Th i s t he rapy ca n be u se fu l fo r pa t i e n t s w i th MR I and c l i n i c a lev idence o f m i ld ce r eb r a l i nvo lvemen t , t hough i t s u se i s l im i t ed by s eve r a l f a c to r s . I t i s r e commended on l y fo r boys o r ado l e scen t s

w ho have ev ide nce o f a c t i ve i n f l a mma to ry ce re b ra l de mye l i na t iontha t i s s t i l l i n i t s e a r l y s t age s . Because o f i t s mu l t i p l e r i sk s t hep r ocedur e i s no t r ecommended fo r young pa t i en t s who have noev idence o f c e r eb r a l i nvo lvemen t . The ba s i s o f t he p r ocedur e i sde sc r ibed i n f i gu r e one on the fo l l ow ing page .
http://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapyhttp://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapyhttp://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapyhttp://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapyhttp://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapyhttp://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapyhttp://marrow.org/Patient/Disease_and_Treatment/About_Your_Disease/Metabolic_Disorders/Cerebral_X-Linked_ALD.aspx#HormoneReplacementTherapy


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F igu r e one : The ba s i s o f HSC Tr ansp l an t .

(Add i t i ona l i n fo : h t tp ://www.x - a ld .n l/ t r ea tmen t -op t ions/hsc t/)

Dieta ry r es t r i c t ion and inh ib i t ion o f endogenous syn thes i s o f VLCFAs

The de mo nst r a t i on tha t t he abnor ma l a cc umul a t i on of VL C FA s i sthe p r inc ip l e b iochemica l abnor ma l i t y i n X-ALD l ed to thein t r oduc t ion o f d i e t a r y t he r apy a imed to r educe VLCF A l eve l s . Thef i r s t a t t empt s i nvo lved the s t r i ngen t r educ t ion o f VLCF A in t ake v i ad i e t , howeve r , p l a sma C26 :0 l eve l s r ema ined una l t e r ed and the r e

wa s no e f f ec t on c l i n i c a l p rog re s s io n . Th i s l e d to s c i en t i s t s a ndc l i n i c i an s t o be l i eve tha t VLCF As wer e no t on l y t aken in v i a d i e t ,bu t a l so p r oduced v i a enzymat i c r e ac t i ons i n t he body , t e r medb io syn thes i s ( S ee f i gu r e two ) .
http://www.x-ald.nl/treatment-options/hsct/http://www.x-ald.nl/treatment-options/hsct/http://www.x-ald.nl/treatment-options/hsct/


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F igu r e two : Norma l i n d i v id u a l an d a pa t i en t w i t h ALDsu pp l emen t ed w i t h Loren zo s O i l . Not e t h a t bo t h d i e t an db io syn thes i s a r e r educed , a s d i sp l a yed by the r ed c r o s se s .

Lo r enzo s Oi l Ther apy

Upon the numer ous t r i a l s , i n c lud ing one by R i zzo e t a l . ( 1984 ) ,d im in i sh ing the s yn thes i s o f s a tu r a t ed VLCF As by ove r lo ad ing thebody w i th unsa tu r a t ed VLCF As such a s o l e i c a c id (C18 :1 ) , i t wasthen de t e r m ined tha t e r uc i c a c id (C22 :1 ) o f f e r ed add i t i ona l e f f i c acy .

Th i s l ed to the de ve lopme n t o f a 4 : 1 m ix tu re o f g l y c e r y l t r i o l e a t ean d g l y ce ry l t r i e ru ca t e , su bseq u en t l y n amed Loren zo s O i l ; a f t e r aboys pa r en t s who wor ked w i th s c i en t i s t s t o deve lop the o i l .

The a dmin i s t r a t i on o f th i s mi x t u re wa s r epo rt e d to no r ma l i z ep l a sma C26 :0 l eve l s w i th in fou r weeks . Th i s l ed to a s e r i e s o f c l i n i c a l t r a i l s , wh i ch had va r ious ou t comes . On the ba s i s o f t heda t a a ch i eved f r om the numer ous t r i a l s , s t i l l o ccu r r ing today , i t i shypo thes i zed tha t l ower ing p l a sma C26 :0 l eve l s l ower s t he r i sk o f ch i l dhood ce r eb r a l X -ALD, bu t t he p r even t ion i s no t ab so lu t e . Themechan i sm o f t he p r even t a t i v e e f f ec t i s i n comp le t e l y unde r s toodowing to ou r i n ab i l i t y t o measu r e C26 :0 l eve l s i n v i v o ( i n t he body ,r a the r t han i n v i t r o ; i n t e s t t ube ) (Mose r , e t a l . , 2007 ) .

(Add i t i ona l i n fo :h t tp :// r a r ed i s ea se s . abou t . com/cs/a ld/a/041301 .h tm)
http://rarediseases.about.com/cs/ald/a/041301.htmhttp://rarediseases.about.com/cs/ald/a/041301.htmhttp://rarediseases.about.com/cs/ald/a/041301.htm


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Other po ten t ia l the rapy op t ions fo r Adreno leukodys t rophy

A va r i e t y o f o the r po te nt i a l t he ra p i e s fo r X -ALD ha ve beensugges t ed .

4 -Ph e n y l bu t y r a t e , a p r od r ug , a c t i v a t ed on l y once me t abo l i z ed i n t hel i v e r i n to pheny l ace t a t e , wh i ch ac t i v e l y i nh ib i t s an enzyme(meva lona t e py r ophospha t e deca r boxy l a se ) , h a s been o f i n t e r e s tbecause o f t he s t ud i e s by Kemp e t a l . ( 1998 ) . They showed tha t 4 -P heny lbu t y r a t e i n c r ea se s t he c apac i t y o f cu l t u r ed sk in f i b r ob l a s t so f X-ALD pa t i en t s t o me t abo l i z e VLCF As v i a o the r enzymesinh ib i t ed i n t he p r e sence o f meva lona t e py r ophospha t edeca r boxy l a se , r e su l t i ng i n t he no r ma l i z a t i on o f VLCF A l eve l s

w i th in the se cu l t u r e s . Howe ve r , t he mec han i sm of a c t i on i s n ot y e tc l e a r . Resea r ch con t inues .

Lov a s t a t i n , a t ype o f S t a t i n o f t en u sed to t r e a t d y s l i p id aemia , h a sbeen admin i s t e r ed because o f i t s f avour ab l e e f f ec t on VLCF Ametabo l i sm in X-ALD f ib r ob l a s t s comb ined w i th i t s an t i -i n f l ammato r y a c t i on (Kwak e t a l . , 2000 ) . A s t udy by P a i e t a l . (2000)r epo r t ed tha t l ova s t a t i n i s ab l e t o l ower VLCF A l eve l s i n pa t i en t s ,howeve r Ca r t i e r e t a l . ( 2000 ) d id no t deno t e such f i nd ings w i th inX-ALD mouse mode l s .

Enz ym e r e p l a c em en t t h e r a p y (ER T) . R . Br ady specu l a t ed i n 1966 tha t i f an enzyme wer e i n su f f i c i en t l y a c t i v e , one m igh t a t t empt to pu r i f y i tand in j ec t i t i n to pa t i en t s t o s ee i f i t wou ld p r ov ide the r apeu t i c

bene f i t (Br ady , 1966 , 1967 ) . The f i r s t i nves t i g a t i on a long th i s l i n ewa s the i n t r ave nous i n j e c t io n o f he xosa mi n i da se A in t o a n i n fa n tw i th Tay -Sa chs d i s ea se , su ch pa t i e n t s a c cumu l a t e t he g nag l i o s i de ,GM2 , i n t he b r a in and g lobos ide i n pe r iphe r a l t i s sue s and the b lood .( Johnson e t a l . , 1973 ) . A s i gn i f i c an t r educ t ion o f g lobos ideoccu r r ed i n t he c i r cu l a t i on sho r t l y a f t e r i n fu s ing the enzyme .However , none o f t he enzyme r eached the b r a in , f a i l i ng to pa s s t heb lood -b r a in ba r r i e r . The pa t i en t a l so expe r i enced P y r ex i a ( h i ght emper a tu r e ) fo l l ow ing i n fu s ion , and the r e was no change to thepa t i en t s c l i n i c a l con d i t i on . To da t e , ERT has p r ov ided no r epo r t edc l e a r bene f i t s i n pa t i en t s who have Leukodys t r ophy . However ,

g i ven i t s p r omi se , ERT i s cu r r en t l y unde r i nves t i g a t i on i nmet ach r omat i c and g lobo id ce l l Leukodys t r oph i e s .

Future deve lopment

I t i s c r uc i a l t o men t ion tha t advancemen t i n t he r apeu t i c s w i l ld epend upon in t e r na t iona l mu l t i c en t r e co l l abo r a t i ons , an i d ea tha t

wa s s t ro ng l y p romul ga ted by Hugo Mose r . T h i s re qu i r e s t hee s t ab l i shmen t o f a comp lex i n f r a s t r uc tu r e , wh i ch i nc ludese l ec t r on i c d a t abase s fo r c l i n i c a l , g ene t i c , l abo r a to r y , and

neur o imag ing da t a . Mose r and co l l abo r a to r s showed tha t s t r uc tu r e scou ld be e s t ab l i shed w i th moder n , nex t - gene r a t i on In t e r ne t


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t e chno logy and enhance i n fo r ma t ion be tween in s t i t u t i ons . I t i sexpec t ed tha t w i th the advancemen t o f compute r t e chno logy the set ypes o f mu l t i c en t r e d a t abase s w i l l b ecome fea s ib l e and a l l ow theconduc t o f mu l t i p l e t he r apeu t i c t r i a l s .

REF ERENCES :

Br ady ( 1966) The sp h i ng o l ip id o se s . N En g l J Med . 275 :312 -318 .

Br ady ( 1967) E nzym a t i c ab no r ma l i t i e s i n d i se a se s o f s ph in go l i p idme t abo l i sm . Cl i n Ch em . 13 :565 -577 .

Ca r t i e r , e t a l . ( 2000 ) S imvas t a t i n d oe s n o t n orma l i z e v e ry l on g ch a in f a t t y a c i d s i n Ad ren o l eu kod ys t roph y mice . FEBS Le t t e r .478 (3 ) : 205 -208 .

J ohns on , e t a l . ( 19 73 ) In t r aven ou s i n j e c t i on o f pu r i f i edhexosamin ida se A in to a p a t i en t w i th Tay - S ach s d i s e a se . B i r t h De f e c t s O r i g Ar t i c S e r . 9 :120 -124 .

Kemp , e t a l . ( 1998 ) Gen e r ed u n d an cy an d ph a rmaco log i c a l g en et he r apy : imp l i c a t i ons fo r X- l i nked Adr eno l eukodys t r ophy . Na t .

Med . 4 (11 ) : 1261 -1268 .

Kwak , e t a l . ( 2000 ) S t a t i n s a s a n ew l y r e cogn i s ed t ype o f immu n omod u l a t o r . Na t . Med . 6 (12 ) : 1399 -1402 .

Mose r , e t a l . ( 2007 ) Loren zo s o i l t h e r apy fo r X - l i nkedA dreno l e uk ody s t rophy : r a t i ona l e and c u r r en t a s se s s men t o fe f f i c a cy . J Mo l Neu r o s c i . 33 :105 -113 .

P a i , e t a l . ( 2000 ) Lovas t a t i n t h e r apy fo r X - l i nkedA dreno l e uk ody s t rophy : c l in i c a l an d b ioche mi ca l ob se rva t i ons on 12pa t i en t s . Mo l . G en e t . Me ta b . 69 (4 ) : 312 -322 .

Raymond , e t a l . ( ed s ) ( 2011 ) Leu kod ys t roph i e s . In t e rn a t i on a lRev i ew o f Ch i l d Neur o logy Se r i e s . Mac Ke i th P r e s s : London , UK.

R izzo , e t a l . ( 1984 ) Ad ren o l eu kod ys t roph y ve r y l ong - cha in f a t t y -ac id me t abo l i sm in f i b rob l a s t s . Neu r o l o g y. 34 ( 2 ) : 163 -169 .

A DDI TI ONAL WEBSI TE S:

S top ALD founda t ion :h t tp ://www. s topa ld .o r g/a ld/Tr ea t i ngALD.asp

NINDS ALD in fo page :h t tp ://www.n inds .n ih . gov/d i so r de r s/ad r eno l eukodys t r ophy/ad r eno

l eukodys t r ophy .h tm#Is_ the r e_any_ t r ea tmen t
http://www.stopald.org/ald/TreatingALD.asphttp://www.stopald.org/ald/TreatingALD.asphttp://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm#Is_there_any_treatmenthttp://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm#Is_there_any_treatmenthttp://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm#Is_there_any_treatmenthttp://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm#Is_there_any_treatmenthttp://www.ninds.nih.gov/disorders/adrenoleukodystrophy/adrenoleukodystrophy.htm#Is_there_any_treatmenthttp://www.stopald.org/ald/TreatingALD.asp


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current ald therapeutic options

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