In 1996, Dr. Meikle was co-recipient of a National Health and Medical Research Council, Program Grant entitled Lysosomal Storage Disorders: Diagnosis, Treatment and Lysosomal Function. This Program has recently been renewed for the period 2000-2004 (Chief Investigators; Prof. J. Hopwood, Dr. D. Anson, Dr. D. Brooks, and Dr. P. Meikle). Research Support is also obtained from commercial collaborators, in particular Pharming BV and TLH Research who are supporting the development of newborn screening for lysosomal storage disorders. Within the framework of the NH&MRC funded Program Grant and in collaboration with other members of the Program, Dr. Meikle has interests and active research projects in the areas of:
Newborn Screening for Lysosomal Storage Disorders
In recent years treatment of some lysosomal storage disorders (LSD) has become possible and it is probable that within the next 5 to 10 years effective therapies will be available for a number of LSD. The effectiveness of these therapies, particularly those for disorders involving the central nervous system, will rely heavily upon early, pre-symptomatic detection of the disorder. We are working towards the development of procedures that will enable the mass screening of all newborns for all lysosomal storage disorders.
Patient Evaluation and Monitoring of Therapy for Lysosomal Storage Disorders
With the development of new therapies for many lysosomal storage disorders (LSD), the diagnostic requirements for these disorders are changing. The efficacy of many of the proposed therapies will rely heavily upon early detection and treatment, before the onset of irreversible pathology. Improved diagnostic procedures and newborn screening for LSD promises to provide such early detection, however pre-symptomatic diagnosis raises a number of issues relating to patient management and treatment. Ideally, therapy should be commenced prior to the onset of pathology, however the wide clinical spectrum displayed in many LSD will make selection of therapy options difficult unless additional information relating to disease progression can be determined. The establishment of dose requirements for either drug or enzyme replacement therapies will be uncertain and therefore hazardous without some detail as to clinical severity. In addition, methods to monitor the effects of therapy in a clinically unaffected individual will be required.
These issues are being addressed in our current research program.
Meikle PJ and Hopwood JJ. (2002) Lysosomal storage disorders: Early diagnosis and effective therapy. Eur J Paed In Press.
Meikle PJ and Hopwood JJ. (2002) Newborn screening for lysosomal storage disorders:Issues and Strategies. Current Medical Literature, Lysosomal Storage Diseases with focus on Fabry disease In Press.
Whitfield PD, Nelson P, Sharp PC, Bindloss CA, Dean C, Ravenscroft EM, Fong BA, Fietz MJ, Hopwood JJ and Meikle PJ. (2002) Correlation between genotype, phenotype and biochemical markers in Gaucher disease: Implications for the prediction of disease severity. Mol Genet Metab 75(1):46-55.
Rozaklis T, Ramsay SL, Whitfield PD, Ranieri E, Hopwood JJ and Meikle PJ. (2002) Determination of oligosaccharides in Pompe disease by electrospray ionisation tandem mass spectrometry. Clin Chem 48:131-139.
Berg T, King B, Meikle PJ, Nilssen O, Tollersrud OK and Hopwood JJ. (2001) Purification and characterization of recombinant human lysosomal alpha-mannosidase. Mol Genet Metab 73(1): 18-29.
Raben N, Lu N, Nagaraju K, Rivera Y, Lee A, Yan B, Byrne B, Meikle PJ, Umapathysivam K, Hopwood JJ and Plotz PH. (2001) Conditional tissue-specific expression of the acid alpha-glucosidase (GAA) gene in the GAA knockout mice: implications for therapy. Hum Mol Genet 10(19): 2039-2047.
Umapathysivam K, Hopwood JJ and Meikle PJ. (2001) Determination of acid alpha-glucosidase activity in blood spots as a diagnostic test for Pompe disease. Clin Chem 47(8): 1378-1383.
Whitfield PD, Sharp PC, Taylor R, Meikle P. (2001) Quantification of galactosylsphingosine in the twitcher mouse using electrospray ionization-tandem mass spectrometry. J Lipid Res 42:2092-2095.
Whitfield PD, Sharp PC, Johnson DW, Nelson P and Meikle PJ. (2001) Characterization of urinary sulfatides in metachromatic leukodystrophy using electrospray ionization-tandem mass spectrometry. Mol Genet Metab 73(1): 30-37.
Chang MH, Bindloss CA, Grabowski GA, Qi X, Winchester B, Hopwood JJ and Meikle PJ. (2000) Saposins A, B, C, and D in plasma of patients with lysosomal storage disorders. Clin Chem 46(2): 167-174.
Isaac EL, Karageorgos LE, Brooks DA, Hopwood JJ and Meikle PJ. (2000) Regulation of the lysosome-associated membrane protein in a sucrose model of lysosomal storage. Exp Cell Res 254(2): 204-209.
Meikle PJ and Hopwood JJ. (2000) Lysosomal storage disorders: Incidence and newborn screening. Gaucher Clinical Perspectives 8(1): 1-5.
Umapathysivam K, Whittle AM, Ranieri E, Bindloss C, Ravenscroft EM, van Diggelen OP, Hopwood JJ and Meikle PJ. (2000) Determination of acid alpha-glucosidase protein: evaluation as a screening marker for Pompe disease and other lysosomal storage disorders. Clin Chem 46(9): 1318-1325.
Meikle PJ, Ranieri E, Ravenscroft EM, Hua CT, Brooks DA and Hopwood JJ. (1999) Newborn screening for lysosomal storage disorders. Southeast Asian J Trop Med Public Health 30 Suppl 2:104-110.
Meikle PJ, Yan M, Ravenscroft EM, Isaac EL, Hopwood JJ and Brooks DA. (1999) Altered trafficking and turnover of LAMP-1 in Pompe disease-affected cells. Mol Genet Metab 66(3): 179-188.
Ranierri E, Gerace RL, Ravenscroft EM, Hopwood JJ and Meikle PJ. (1999) Pilot neonatal screening program for lysosomal storage disorders, using lamp-1. Southeast Asian J Trop Med Public Health 30 Suppl 2:111-113.
Chataway TK, Whittle AM, Lewis MD, Bindloss CA, Davey RC, Moritz RL, Simpson RJ, Hopwood JJ and Meikle PJ. (1998) Two-dimensional mapping and microsequencing of lysosomal proteins from human placenta. Placenta 19(8): 643-654.
Chataway TK, Whittle AM, Lewis MD, Bindloss CA, Moritz RL, Simpson RJ, Hopwood JJ and Meikle PJ. (1998) Development of a Two-Dimensional Gel Electrophoresis Database of Human Lysosomal Proteins. Electrophoresis 19:834-836.
Hua CT, Hopwood JJ, Carlsson SR, Harris RJ and Meikle PJ. (1998) Evaluation of the lysosome-associated membrane protein LAMP-2 as a marker for lysosomal storage disorders. Clin Chem 44(10): 2094-2102.
Karageorgos LE, Isaac EL, Brooks DA, Ravenscroft EM, Davey R, Hopwood JJ and Meikle PJ. (1997) Lysosomal Biogenesis in Lysosomal Storage Disorders. Experimental Cell Research 234:85-97.
Meikle PJ, Brooks DA, Ravenscroft EM, Yan M, Williams RE, Jaunzems AE, Chataway TK, Karageorgos LE, Davey RC, Boulter CD, Carlsson SR and Hopwood JJ. (1997) Diagnosis of lysosomal storage disorders: evaluation of lysosome-associated membrane protein LAMP-1 as a diagnostic marker. Clin Chem 43(8 Pt 1): 1325-1335.
