Research Program

The research program carried out in the Lysosomal Diseases Research Unit remains a major initiative within the hospital and is primarily funded by a Program Grant from the National Health & Medical Research Council (NH&MRC) of Australia. Funding from all sources totals A$1.2 M per annum and supports a team of 40 workers, including 11 post graduate students studying towards higher degrees in the area of research within the lysosomal area. The Chief Investigators in the Unit headed by Professor John Hopwood are Dr. Don Anson, Dr. Doug Brooks, Dr. Sharon Byers, Dr. Peter Clements and Dr. Peter Meikle.

The current major areas of research include:

• Screening newborns for LSD - Early detection of these diseases is imperative to enable treatment to begin at birth so that damaging irreversible pathologies do not occur.
• Isolation of genes involved in LSD - We have isolated a number of LSD genes over the past eight years and including the isolation of two genes involved in a particularly severe and aggressive LSD known as Sanfilippo syndrome. These are common disorders, devastating to families, and now with the gene isolated, we are hopeful that we will be able to develop gene and enzyme replacement therapies.
• Developing enzyme replacement therapies to treat LSD patients - These studies have advanced to stage where clinical trials are likely within the next two years for several of these disorders. However, our research dealing with the passage of enzymes in circulation into the brain is of immediate importance.
• Developing gene replacement therapies - Unlike enzyme replacement therapy there are still a number of technical problems to overcome before this form of therapy can be widely used to treat LSD patients. Our research focuses on solving these problems.
• Investigation of the process of bone growth - Little is known about the process of normal and pathological bone growth . Our group, in collaboration with the Bone Growth Foundation at the Women's and Children's Hospital, is working to achieve a better understanding of bone disorders, particularly as they relate to children with LSD.
• Determination of tertiary structure of lysosomal proteins - We are currently investigating the structure of enzymes involved in the hydrolysis of mucopolysaccharides. These studies will enable us to understand the mechanism of action of individual hydrolases towards their specific substrates.
• Regulation, biogenesis and function of lysosomes - A number of studies are currently underway concerned with the basic biology of lysosomes in normal and pathological conditions.

Major Collaborations

Extensive collaborations exist between the Unit and scientific researchers, clinicians and organisations both nationally and internationally. See the publications below for examples of these collaborations.

1996 Visiting Research Fellows

Professor Bertram Ponz, Munich, Germany
Dr. Elena Voskoboeva, Moscow, Russia
Dr. Tommaso Beccari, Perugia, Italy

Commercialisation of Research

A very necessary activity to take advantage of innovation developed from the above research to achieve clinical trials of therapies and the introduction of new diagnostic methods for LSD patients. It is not possible to achieve the Unit goals concerned with therapy without commercialisation. The Unit has currently licensed a number of its patented innovations to international companies.

Postgraduate Students

John Hopwood is currently co-supervising eleven postgraduate students (PhD, MSc and MD) working within the Unit.

Publications

420 research papers, conference proceedings and reviews in biomedical and organic chemical research: biochemical genetics, biochemistry, organic chemistry and polymer science. 17 world wide patents.

Examples of recent publications

HOPWOOD, J J., BUNGE, S., MORRIS, C.P., WILSON, P.J., STEGLICH, C. BECK, M., SCHWINGER, E. and GAL, A. Molecular basis of mucopolysaccharidosis type II: mutations in the iduronate-2-sulphatase gene. (1993) Human Mutations. 2: 435-442.
HOPWOOD JJ, VELLODI A, SCOTT HS, MORRIS CP, LITJENS T, CLEMENTS PR, BROOKS DA, COOPER A and WRAITH JE. Long-term clinical progress in bone marrow transplanted mucopolysaccharidosis type I patients with a known genotype. (1993) Journal Inherited Metabolic Diseases. 16: 1024-1033.
ISBRANDT, D., ARLT, G., BROOKS, D.A., HOPWOOD, J.J., von FIGURA, K. and PETERS, C. Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): six unique arylsulfatase B gene alleles causing variable disease phenotypes. (1994) American Journal of Human Genetics. 54: 454-463.
UNGER, E.G., DURRANT, J., ANSON, D.S. and HOPWOOD, J.J. Recombinant *-L-iduronidase: characterisation of the purified enzyme and correction of mucopolysaccharidosis type I fibroblasts. (1994) Biochemical Journal. 304: 43-49.
ASHBY, SJ, CLEMENTS PR, GUSS M, HARVEY I and HOPWOOD JJ. Crystallisation and preliminary characterisation of human recombinant N-acetygalactosamine-4-sulfatase. (1995) Acta Crystallography. 51: 1082-1083.
BROOKS DA, ROBERTSON DA, BINDLOSS C, LITJENS T, ANSON D, PETERS C, MORRIS CP and HOPWOOD JJ. Two site-directed mutations abrogate enzyme activity but have different effects on conformation and cellular content of N-acetygalactosamine-4-sulfatase protein. (1995) Biochemistry Journal. 307: 457-463.
FULLER M, VAN DER PLOEG A, REUSER AJJ, ANSON DS and HOPWOOD JJ. Isolation and characterisation of a recombinant, precursor form of lysosomal acid alpha-glucosidase. (1995) European Journal of Biochemistry. 234: 903-909.
SCOTT, H.S., BUNGE, S., GAL, A., CLARKE, L.A., MORRIS, C.P. and HOPWOOD, J.J. The molecular genetics of mucopolysaccharidosis type I: diagnostic, clinical and biological implications. (1995) Human Mutations. 6: 288-302.
SCOTT, H.S., BLANCH, L., GUO, X-H., FREEMAN, C., ORSBORN, A., BAKER, E., SUTHERLAND, G.R., MORRIS, C.P. and HOPWOOD, J.J. Cloning of the sulphamidase gene and identification of mutations in Sanfilippo A syndrome. (1995) Nature Genetics. 11: 465-468.
SALVETTI, A., MOULLIER, P., CORNET, V., BROOKS, D., HOPWOOD, J.J., DANOS, O. and HEARD, J-M. In vivo delivery of human a-L-iduronidase in mice implanted with neo-organs. (1995) Human Gene Therapy. 6: 1153-1159.
LITJENS T, BROOKS DA, PETERS C, GIBSON GJ and HOPWOOD JJ. Identification, expression, and biochemical characterisation of N-acetylgalactosamine-4-sulfatase mutations and relationship with clinical phenotype in MPS-VI patients. (1996) American. Journal of Human Genetics. 58: 1127-1134.
CRAWLEY AC, BROOKS DA, MULLER VJ, PETERSEN BA, ISAAC El, BIELICKI J, KING BM, BOULTER CD, MOORE AJ, FAZZALARI NL, ANSON DS, BYERS S and HOPWOOD JJ. Enzyme replacement therapy in a feline model of Maroteaux-Lamy syndrome. (1996) Journal of Clinical Investigation. 97: 1864-1873.
TSUDA H, YAMADA S, YAMANE Y, YOSHIDA K, HOPWOOD JJ and SUGAHARA, K. Structures of Five Sulfated Hexasaccharides prepared from Porcine Intestinal Heparin using Bacterial Heparinase: Structural Variants with apparent Biosynthetic Precursor-Product Relationships for the Antithrombin III-Binding Site. (1996) Journal of. Biological. Chemistry. 271: 10495-10502.
FAIRBAIRN LJ, LASHFORD LS, MCDERMOTT RH, SPOONER E, ARRAND JE, ARRAND JR, BELLANTUONO I, HOLT R, LEBENS G,HATTON CE, COOPER A, BESLEY GTN, WRAITH JE, ANSON DS, HOPWOOD JJ and DEXTER TM. Long-term in vitro correction of alpha-L-iduronidase deficiency (Hurler's syndrome) in human bone marrow. (1996) Proceedings of the National Academy of Sciences USA. 93:2025-2030
WEBER, B., BLANCH, L., CLEMENTS, P.R., SCOTT, H.S. and HOPWOOD, J.J. Cloning and expression of the gene involved in Sanfilippo B syndrome (mucopolysaccharidosis IIIB). (1996) Human Molecular Genetics. 5: 771-777.

Contact

Professor John Hopwood,
Head,
Lysosomal Diseases Research Unit,
Women's and Children's Hospital,
72 King William Road,
North Adelaide,
South Australia 5006
Australia