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ENZYME REPLACEMENT THERAPIES
FOR LYSOSOMAL STORAGE DISEASES
Maria Francisca Coutinho
Lysosomal Storage Disorders Group
Research & Development Unit,
Department of Human Genetics,
INSA
Semmelweis Symposium 2018
8th-9th November, 2018
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LYSOSOMAL STORAGE DISORDERS (LSDS)
Genetic
Rare
Autosomal recessive (majority)
Portugal - 1/4000
Almost 70!
9th November, 2018
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LYSOSOMAL STORAGE DISORDERS (LSDS)
Chronic
Progressive
Large spectrum of severity
& symptoms
CNS pathology is a common hallmark of
LSDs
LSDs are the commonest cause of
paediatric neurodegenerative disease9th November, 2018
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LYSOSOMAL STORAGE DISORDERS (LSDS)
Chronic
Progressive
Large spectrum of severity
& symptoms
(from in utero/paediatric
to late adult onset forms)
Pathophysiology
still unknown!
9th November, 2018
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LYSOSOMAL STORAGE DISORDERS (LSDS)
9th November, 2018
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LYSOSOMAL STORAGE DISORDERS (LSDS)
9th November, 2018
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Progressive accumulation
LYSOSOMAL STORAGE DISORDERS (LSDS)
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Progressive accumulation
LYSOSOMAL STORAGE DISORDERS (LSDS)
?
9th November, 2018
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1969
Elizabeth Neufeld
THE ENZYME AS A DRUG?
9th November, 2018
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trans
face
clathrin coat
transport vesicle
Late Endosome/
Lysosome
plasma membrane
THE ENZYME AS A DRUG?
9th November, 2018
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trans
face
clathrin coat
transport vesicle
Late Endosome/
Lysosome
plasma membrane
THE ENZYME AS A DRUG?
CI-MPR
clathrin-mediated
endocytosis
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trans
face
clathrin coat
transport vesicle
Late Endosome/
Lysosome
plasma membrane
THE ENZYME AS A DRUG?
CI-MPR
clathrin-mediated
endocytosis
Enzyme Replacement
Therapy
9th November, 2018
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PROOF OF PRINCIPLE…
Gaucher Disease (GD)
Deficient enzyme: -glucocerebrosidase
Gene: GBA (1q21)
Most frequent LSD
Original illustration by Marcos Bernardino for
Cristiana Petriz´s “Gigi e a Doença de Gaucher”, 20109th November, 2018
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PROOF OF PRINCIPLE…
Gaucher Disease (GD)
Deficient enzyme: -glucocerebrosidase
Gene: GBA (1q21)
Missing enzyme
isolated from human
placentae
o IV injection into patients
o extraordinary results
in blood tests!
Original illustration by Marcos Bernardino for
Cristiana Petriz´s “Gigi e a Doença de Gaucher”, 20109th November, 2018
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PROOF OF PRINCIPLE…
Gaucher Disease (GD)
Deficient enzyme: -glucocerebrosidase
Gene: GBA (1q21)
Intravenous injections of the
recombinant enzyme
Excellent results in systemic
disease
Original illustration by Marcos Bernardino for
Cristiana Petriz´s “Gigi e a Doença de Gaucher”, 2010
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THE ENZYME AS A DRUG?
Pathology Available ERT
Gaucher Cerezyme® VPRIV® Elelyso®
(Imiglucerase; Genzyme) (Velaglucerase alfa; Shire) (Taliglucerase alfa; Pfizer)
Fabry Replagal® Fabrazyme®
(Agalsidase alfa; Shire) (Algalsidase beta; Genzyme)
MPS I Aldurazyme®
(Laronidase; Genzyme)
MPS II Elaprase®
(Idursulfase; Shire)
MPS IV A Vimizim®
(Elosulfase alfa; Biomarin)
MPS VI Naglazyme®
(Galsulfase; Biomarin)
Pompe Myozyme®
(Lumizyme, Alglucosidase alfa; Genzyme)
LAL
deficiency
Kanuma®
(Sebelipase alfa; Alexion)9th November, 2018
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Several limitations
Cost
Lifelong dependance
Ineffective for the CNS manifestations
…antibodies?
…secondary effects?
THE ENZYME AS A DRUG?
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FabryMucopolysaccharidosis
type I
Sialidosis
Galactosialidosis
MPS IIIAMPS IIIBKrabbe
Mucolipidosis
type II
Tay–Sachs
Metachromatic
leukodystrophy
Multiple sulfatase
deficiency
SandhoffMPS IVA
MPS IVB
Fucosidosis
Alpha-
mannosidosis
Beta-mannosidosisPycnodysostosis
Danon
Wolman
GaucherNiemann-Pick
type CPompe MPS II
MPS IIICML III
FarberGaucher+ 70 diseases
most has no treatment!
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STILL SO MUCH TO DO…
9th November, 2018
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STILL SO MUCH TO DO…
FabryGaucher
PompeGaucher“With research,
possibilities are limitless”…
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enzyme replacement therapies
more effective
able to cross the BBB
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
Final goal: brain
How?
intrathecal injection
(into the spinal canal/subarachnoid space so that it
reaches the cerebrospinal fluid (CSF))
Clinical trials:
MPS I
MPS II
MPS IIIA
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Final goal: brain
How?
intracerebroventricular injections
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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Final goal: brain
How?
intracerebroventricular injections
Clinical trials:
MPS IIIB
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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Final goal: brain
How?
intracerebroventricular injections
intrathecal
Associated risks!
infections
cirurgical procedures
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
Final goal: brain
How?
Better vectors
Modified viruses (non-pathogenic)
retrovirusess (RNA)
adenoviruses (DNA)
lentiviruses
‘adeno-associated’ viruses(AAV)
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“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
Final goal: brain
How?
Molecular ‘Trojan-horses’
+ signal-peptides
‘receptor-mediated transport’
insulin
apolipoprotein
…
9th November, 2018
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‘Broader’ approaches
i.e. 1 therapy 1 disease
(or even more!)
‘Personalized’ approaches
i.e. 1 therapy for each mutation/
type of mutation
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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‘Broader’ approaches
enzyme replacement therapies
more effective
able to cross the BBB
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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‘Broader’ approaches
gene therapy
Clinical trials:
Metachromatic leukodystrophy
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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‘Broader’ approaches
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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‘Broader’ approaches
Genetic substrate reduction
“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
9th November, 2018
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“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
‘Personalized’ approaches
Final goal:
correction/amellioration of 1 mutation in particular
type of mutations
How?
Molecular chaperones
stabilize mutant proteins
promote their transport into the lysosome
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AS POSSIBILIDADES (ILIMITADAS) DA
INVESTIGAÇÃO…
‘Personalized’ approaches
Final goal:
correction/amellioration of 1 mutation in particular
type of mutations
How?
Molecular chaperones
GalafoldTM
(Migalastat; Amicus Therapeutics)
9th November, 2018
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“WITH RESEARCH, POSSIBILITIES ARE LIMITLESS”…
‘Personalized’ approaches
Final goal:
correction/amellioration of 1 mutation in particular
type of mutations
How?
Correction of splicing mutations
9th November, 2018
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Our work at PT National Institute of Health…
‘Broader’ approaches
gSRT for MPS
‘Personalized’ approaches
correction of splicing mutations in different LSDs
Common denominator:
Genetic-based therapies
RNA-based
‘Easy’ to test at a cellular level – 1st stage9th November, 2018
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THE FUTURE(S)…
gSRT + enzyme replacement therapy
9th November, 2018
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gene therapy
THE FUTURE(S)…
9th November, 2018
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Personalized therapies
THE FUTURE(S)…
9th November, 2018
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ACKNOWLEDGMENTS
Dr. Sandra Alves
Prof. Mª João Prata
Juliana Inês Santos
Paulo Gaspar
SFRH/BPD/101965/2014
SFRH/BD/124372/2016
bcp/LIM/DGH/Dz2015
António Reis
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THANK YOU!