Improved clinical management of lysosomal disorders
Submitting InstitutionUniversity of Manchester
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Neurosciences, Oncology and Carcinogenesis, Paediatrics and Reproductive Medicine
Summary of the impact
Researchers at the University of Manchester (UoM) characterised fatal
childhood lysosomal storage diseases (LSDs) and developed new treatments.
The research has led to the licensing of 6 drugs worldwide (of a total of
9 available) for LSDs including mucopolysaccharide disease I, II, IIIA,
IVA, VI, Fabry, Pompe and Niemann Pick C. As a result, longevity and
quality of life have improved for more than 800 LSD patients in England
and more than 3000 worldwide. Home enzyme treatment has improved quality
of life for the majority of LSD patients in the UK (>400). The research
has broadened the scope of haematopoietic stem cell transplantation for
LSDs and reduced mortality, benefiting more than 100 LSD patients
UoM researchers are given in bold.
The aims of the research carried out at UoM were to improve the
diagnosis, treatment and management of LSDs. The research was carried out
between 1993 and 2013, with the majority of the work taking place 2005-13.
Key UoM researchers:
Ed Wraith (Honorary Senior Lecturer, 1993-2008; Honorary
Lez Fairbairn (Professor, 1993-2005)
Robert Wynn (Honorary Lecturer, 1998-2007; Honorary Senior
Brian Bigger (Research Fellow, 2006-2008; Senior Research
Fellow, 2008-2013; Reader, 2013-date)
Simon Jones (Honorary Lecturer, 2009-date)
Genetic characterisation of LSDs
Wraith and colleagues have identified several major genetic
mutations in LSDs including mucopolysaccharidosis type II, IV, VI,
Gaucher and Fabry since 1993.
Wraith recognised a poor genotype-phenotype correlation, but as
many patients are from consanguineous backgrounds, Wraith
identified that common mutations followed similar clinical courses,
allowing improved clinical classification of MPS diseases.
Bone marrow transplantation and gene therapy development for MPSI
Wraith, Fairbairn and colleagues characterised outcomes after
haematopoietic stem cell transplantation (HSCT) in MPS I, II and III.
This is the only treatment for some LSDs and led to adoption of HSCT for
MPSI Hurler and discontinuation for MPSII and III.
- A retroviral HSCT gene therapy approach was adopted for MPSI Hurler
which resulted in an unsuccessful clinical trial in Manchester in 1997.
Natural history studies on LSDs
- Several natural history studies on MPSI (MPSI Registry), MPSII (Hunter
outcome survey), MPSIII, MPSIVA (MOR001), MPSVI (Clinical Surveillance
Program), alpha mannosidosis (Alpha-man), were led in Manchester or with
significant contributions from Wraith, Jones and
Wraith, Bigger, Jones and colleagues validated
biomarkers of lysosomal diseases including dermatan sulphate chondroitin
sulphate ratio and HCIIT against clinical outcomes in
Treatment development for LSDs
Wraith and Jones were co-investigators on clinical
trials evaluating enzyme replacement therapy for MPSI, MPSII, MPSVI,
Fabry, and Pompe disease, and the substrate reduction therapy drug
miglustat for Niemann Pick C.
Jones is co-investigator in ongoing enzyme replacement therapy
trials for MPSIIIA, MPSIIIA-C, MPS IVA and Wolman.
- 6 licensed drugs resulted from this work and Wraith and
colleagues demonstrated that enzyme replacement therapy for MPSII and VI
could be given safely at home.
Wraith, Bigger, Jones, Wynn developed
the substrate reduction therapy drug genistein for MPSIII (trial
starting January 2014) and HSCT gene therapy for MPSIIIA (trial starting
Wraith, Wynn, Bigger and colleagues showed HSCT
to be more effective than enzyme replacement therapy in MPSI, which has
significantly improved transplantation mortality in MPSIH and in a
pan-European HSCT policy, and broadened the indication of HSCT to
include more LSDs.
References to the research
The research was published in the top metabolic journals of the field.
1. Wraith JE, Clarke LA, Beck M, Kolodny EH, Pastores GM, Muenzer
J, Rapoport DM, Berger KI, Swiedler SJ, Kakkis ED, Braakman T, Chadbourne
E, Walton-Bowen K, Cox GF. Enzyme replacement therapy for
mucopolysaccharidosis I: a randomized, double-blinded, placebo-
controlled, multinational study of recombinant human α-L-iduronidase
(laronidase). The Journal of Pediatrics. 2004;144(5):581-8. DOI:
2. Kishnani PS, Corzo D, Nicolino M, Byrne B, Mandel H, Hwu WL, Leslie N,
Levine J, Spencer C, McDonald M, Li J, Dumontier J, Halberthal M, Chien
YH, Hopkin R, Vijayaraghavan S, Gruskin D, Bartholomew D, van der Ploeg A,
Clancy JP, Parini R, Morin G, Beck M, De la Gastine GS, Jokic M, Thurberg
B, Richards S, Bali D, Davison M, Worden MA, Chen YT, Wraith JE.
Recombinant human acid α-glucosidase: Major clinical benefits in
infantile-onset Pompe disease. Neurology. 2007;68(2):99-109. DOI:
3. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE. Miglustat
for treatment of Niemann-Pick C disease: a randomised controlled study. The
Lancet Neurology. 2007;6(9):765-72. DOI:
4. Pastores GM, Arn P, Beck M, Clarke JTR, Guffon N, Kaplan P, Muenzer J,
Norato DYJ, Shapiro E, Thomas J, Viskochil D, Wraith JE. The MPS I
registry: Design, methodology, and early findings of a global disease
registry for monitoring patients with Mucopolysaccharidosis Type I. Molecular
Genetics and Metabolism. 2007;91(1):37-47. DOI:
5. Wynn RF, Wraith JE, Mercer J, O'Meara A, Tylee K, Thornley M,
Church HJ, Bigger BW. Improved Metabolic Correction in Patients
with Lysosomal Storage Disease Treated with Hematopoietic Stem Cell
Transplant Compared with Enzyme Replacement Therapy. The Journal of
Pediatrics. 2009;154(4):609-11. DOI: 10.1016/j.jpeds.2008.11.005
6. Malinowska M, Wilkinson FL, Langford-Smith KJ, Langford-Smith A, Brown
JR, Crawford BE, Vanier MT, Grynkiewicz G, Wynn RF, Wraith JE,
Wegrzyn G, Bigger BW. Genistein improves neuropathology and
corrects behaviour in a mouse model of neurodegenerative metabolic
disease. PLoS One. 2010;5(12):e14192. DOI:
Details of the impact
See section 5 for corroborating sources S1-S9.
Over 70 lysosomal diseases exist with an incidence of 1/7000. They are
progressive, multisystem diseases, usually affecting children, with
severely shortened life expectancy. In 1993 there was one treatment for
LSDs: haematopoietic stem cell transplant. This was only effective in
severe MPSI and had a high procedure-related mortality rate of ~45%. Drug
treatments were slow to appear and individually had limited impact; the
first drug in 1994 for Gaucher disease was cerezyme (imiglucerase), used
for around 80 patients in the UK. In the early 1990s, LSDs were often
diagnosed very late or misdiagnosed and palliative management was
dispersed throughout the UK.
Reach and significance of the impact
Improved clinical management of LSDs
- Several multinational collaborative natural history studies in
Manchester, most of which are still ongoing, resulted in
improved/earlier LSD diagnosis and disease management (S1).
Wraith wrote NHS clinical management guidelines for 6 LSDs
which helped to reduce age of diagnosis in several LSDs including MPSI,
from an average range of 2-10 years of age (2000) to 3 months-4 years of
age (2013), depending on severity (S2). This improvement is important as
early treatment has increased clinical benefit.
- 2005: Manchester was made one of eight National Specialist
Commissioned Centres in England for management and treatment of LSDs
with Wraith (now Jones) as director due to Wraith's
natural history trial background (S3-S6).
- 2010-11 Manchester's recognition as a worldwide centre for LSDs
resulted in Manchester and Wraith handling 15,500 diagnoses per
annum for paediatric inherited metabolic diseases from over 20
countries, of which ~30% are LSDs.
- 2010-11: 1983 LSD patients were managed at 8 NCG centres — 350 in
Enzyme replacement and substrate reduction therapies
Enzyme replacement therapy trials with Wraith/Jones as CI
in Manchester were conducted for the LSDs MPSI, MPSII, MPSVI, Fabry,
and Pompe disease, and the substrate reduction therapy drug miglustat for
Niemann pick C, in collaboration with Biomarin, Shire, TKT, Genzyme,
Actelion and Synageva.
- 2003-13: 6 drugs licensed from these trials in >20 countries
including US, Europe, Canada, Latin America, Japan and Australia (S7).
- 2011-12: 9 licensed drugs for 7 LSDs provided in 8 English NCG centres
for 801 patients with a drug budget of £124 million, 6 of which (~2/3 of
worldwide LSD drug market) were trialled in Manchester by Wraith/Jones
- 2013 >3000 LSD patients in >20 countries worldwide benefited
from drug treatment, ~2/3 from the 6 drugs trialled by Wraith/Jones
- 2013 GALNS for MPSIVA trialled in Manchester (Jones) awaiting
FDA and EMA approval (S7).
Wraith and colleagues have delivered significant quality of
life improvements in patients with these 7 LSDs as a result of their
research, with improvements in cognitive function, muscular, and
skeletal function as well as significantly improved life expectancy of
on average around 10 years or more depending on disease severity.
- Previous life expectancies of a few months in MPSI Hurler disease, is
now considerably extended lifespans of decades, as well as improved
cognitive and/or skeletal outcomes.
Improved haematopoietic stem cell transplantation outcomes
To improve HSCT outcomes, Fairbairn and Wraith developed
retroviral gene therapy in HSCT as a safer and more efficacious
alternative with the world's first LSD gene therapy clinical trial for
MPSIH in Manchester in 1997.
- This trial allowed a more efficacious approach developed by Bigger
and colleagues using a lentiviral vector for MPSIIIA between 2007-13,
expected in clinical trial in 2015.
Wynn and colleagues developed safer HSCT for LSDs. Prior to
1995, 1-2 patients pa were transplanted for MPSIH in Manchester. By
2010, this rose to 7 pa and transplant expanded to other LSDs, including
Niemann Pick CII, resulting in ~10-15 patients transplanted pa (S8, S9).
- Engrafted survival improved from 57% in 1994-2007 to 94% post-2007 and
a demonstration by Wynn, Bigger that HSCT is more effective than
ERT in MPSI disease, with some patients' cognitive development in the
Wynn and colleagues wrote metabolic transplant guidelines for
The European Group for Blood and Marrow Transplantation haematopoietic
stem cell transplant handbook 2008 which include expansion to other
lysosomal diseases (S9).
- Novel biomarkers for LSDs were developed or validated in Manchester
including heparan cofactor II thrombin complex and dermatan sulphate
chondroitin sulphate ratio, both of which correlate with clinical
outcomes in treated patients with MPSI, II and VI.
- Dermatan sulphate chondroitin sulphate ratio has been adopted into
standard clinical disease management in Manchester.
Sources to corroborate the impact
S1. Natural history studies: The MPSI registry (Natural history registry)
; The MPSII Hunter outcome survey (Natural history registry) http://www.globaloutcomesurveys.com/overview.aspx;
Alpha mannosidosis FP7 natural history study http://www.alpha-man.eu/index.htm
S2. Department of Health, National Guidelines for treatment of lysosomal
S3. Advisory Group for National Specialised Services Annual Report,
2011-12 (LSD statistics, p. 82; ERT drug budget, table 10, p. 104; ERT by
disease and drug with patient numbers, England, table 11, p. 105).
S4. Advisory Group for National Specialised Services Annual Report
2010-11 (ERT by disease and drug with patient numbers, England, p. 62; p.
S5. National Specialised Commissioning Priorities 2011-12 (Total LSD
patient numbers in England, p. 45). http://www.specialisedservices.nhs.uk/library/21/National_Specialised_Commissioning_Priorities_201112.pdf
S6. Changes to National Commissioning Group services and NCG
Commissioning intentions 2008-9 (p. 7). http://www.specialisedservices.nhs.uk/library/24/Changes_to_Nationally_Commissioned_S
S7. Companies benefiting directly from the research: Genzyme http://www.genzyme.co.uk/products.aspx;
Shire Human Genetic Therapies www.shire.com/shireplc/en/products/list;
S8. Organisations directly benefiting from the research: UK MPS society
; National MPS Society USA
; Canadian MPS society:
S9. Boelens JJ, Wynn RF, Bierings M. HSCT for inborn errors of
metabolism. In: Apperley J et al., editors. The EBMT-ESH Handbook.
2008. pp. 544-553.