Mucopolysaccharidosis

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Mucopolysaccharidosis Type III (Sanfilippo
Syndrome)
Research Update
Briony Gliddon, Sam Lister Ph.D
scholar Department of Paediatrics, University of
Adelaide Lysosomal Diseases Research Unit,
Chemical Pathology Womens and Childrens Hospital
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Mucopolysaccharidosis type III (MPS III,
Sanfilippo syndrome)

• Lysosomal Storage Disorder (LSD)
• Absence in a lysosomal enzyme needed to break
  down heparan sulphate.
• 4 subtypes of MPS III (A,B,C and D)
• Inherited disorder, characterised by severe CNS
  degeneration
• frequent and severe temper tantrums
• hyperactivity
• aggression
• severe mental retardation

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Therapy for MPS III patients

• No specific therapy
• Bone Marrow Transplantation
• Therapies under investigation
• Enzyme Replacement Therapy (ERT)
• Gene Therapy
• Stem Cell Therapy
• Substrate deprivation

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MPS III Animal models

• MPS IIIA
• Naturally occurring mouse
• 2 canine models
• New Zealand Huntaway dog
• Wire-haired Daschund
• MPS IIIB MPS IIID
• Emu Goat
• Knock out mouse
• Cow

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Enzyme Replacement Therapy in the Mucopolysacchari
dosis type IIIA mice
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NORMAL
MPS IIIA
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The Blood Brain Barrier (BBB)
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The mouse BBB
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AIM
To evaluate whether enzyme that can enter the
brain is effective in preventing/reversing the
pathology observed.
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Learning and memory Test
NE
NW
SW
SE
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Visual Cues
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Long term ERT in MPS IIIA mice

• MPS IIIA mice enzyme treated from birth
• MPS IIIA mice enzyme treated from 6 weeks
• MPS IIIA mice untreated
• Normal mice enzyme treated from birth
• Normal mice untreated

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• Injected 1mg/kg of sulphamidase enzyme weekly
  into the mice.
• 1st injection the superficial temporal vein
• remaining injections the tail vein.
• Duration of study - 20 weeks

Superficial temporal vein
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ERT Results

• Behavioural improvements
• From weaning (3 weeks of age) 5-6 mice were caged
  together.
• Untreated Male MPS IIIA mice and those treated
  from 6 weeks of age had to be separated 10 weeks
  into the trial.
• Male MPS IIIA mice treated from birth had to be
  separated 18 weeks into the trial.
• Normal male mice did not have to be separated
  during the 20 week study.

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Morris Water Maze
100
90
Acquisition
80
Normal untreated
70
Relearning
Normal ERT
60
Reversal
Search Time (Seconds)
MPS IIIA ERT from Birth
50
MPS IIIA ERT from 6wks
40
30
MPS IIIA untreated
20
10
0
2
3
4
5
6
8
9
10
11
12
13
Day
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Day 7, Probe Test
50
45
40
35
30
Search Time (seconds)
Mean target quadrant
25
Mean non-target quadrant
20
15
10
NW
NE
5
0
Normal untreated
Normal ERT
MPS IIIA ERT from Birth
MPS IIIA ERT from 6wks
MPS IIIA untreated

SW
SE
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Summary

• Long term ERT was very successful in the MPS IIIA
  mice, only if initiated early in life.
• Enzyme that can enter the brain is effective in
  reversing pathology. Storage will return if
  enzyme is not regularly supplied to the CNS

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Future Work

• Optimise enzyme dose rate in MPS IIIA mice to get
  maximum efficacy.
• Investigate ways of overcoming the BBB
• Investigate ERT in a larger animal model - the
  MPS IIIA dog

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Acknowledgments
John Hopwood
Dyane Auclair
Animal House Staff
The Lister Family
Lysosomal Disease Research Unit Department of
Chemical Pathology
Allison Crawley