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108. Challenges of LSD treatment: The patient experience
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Abstracts / Molecular Genetics and Metabolism 93 (2008) S14–S46
USA, f University of California, San Francisco, USA, g University of Copenhagen, USA, h University of Alabama at Birmingham, USA, i Mount Sinai School of Medicine, New York City, NY, USA Background: Fabry disease is an X-linked lysosomal storage disorder due to deficient activity of a-galactosidase A causing progressive accumulation of glycolipids, organ damage, and early demise. The progression of renal, cardiac, and cerebrovascular disease in affected males and females has not been well characterized. Methods: An epidemiologic chart review of 447 patients (279 males, 168 females) with untreated Fabry disease from 27 expert sites in the United States and Europe was performed. Prospectively defined study endpoints included renal, cardiac, and cerebrovascular disease progression, and/or death. Results: The mean rate of estimated GFR (eGFR) decline for males (n = 243) and females (n = 152) who did not reach end stage renal disease was 2.93 and 1.02 ml/min/1.73 m2/year, respectively. More rapid eGFR decline was noted in patients with proteinuria, baseline eGFR values <60 ml/min/1.73 m2, or hypertension. Advanced Fabry nephropathy was more prevalent and occurred earlier among males than females. Cardiac events, mainly arrhythmias, occurred in 44% of patients with available information. Stroke (10%) or transient ischemic attacks (5%) were also observed. Conclusions: Proteinuria and/or reduced eGFR at baseline, and hypertension were identified as prognostic factors associated with more rapid progression of the Fabry nephropathy, and can serve as targets for therapeutic intervention. The progression rate of Fabry nephropathy increased with advancing disease. doi:10.1016/j.ymgme.2007.10.118
107. Syngeneic bone marrow transplantation in a murine model of mucopolysaccharidosis type I Daniel A. Wolf a, Kelly M. Podetz-Pedersen a, Jennifer L. Gori a, Walter C. Low b, Chester B. Whitley c, R. Scott McIvor a, a Department of Genetics, Cell Biology, and Development, University of Minnesota-Twin Cities, Minneapolis, MN, USA, b Department of Neurosurgery, University of Minnesota-Twin Cities, USA, c Department of Pediatrics, University of Minnesota-Twin Cities, USA Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited disease caused by deficiency of the glycosidase a-L-iduronidase (IDUA). IDUA is required for the degradation of the glycosaminoglycans (GAG) heparan sulfate and dermatan sulfate, and deficiency of the enzyme leads to lysosomal storage buildup of these substrates. Specific mutations in the IDUA gene (e.g., W402X, Q70X) lead to the most severe phenotype, Hurler syndrome. Manifestations of severe MPS I begin to develop within the first 2 years of life, including growth delay, hepatosplenomegaly, skeletal deformities, excess urinary GAG, corneal clouding, and neurological defects. Recently, IDUA-deficient mouse models of MPS I have become available, providing a setting for evaluation of therapeutic approaches for the treatment of this disease. Currently, the standard of care for severe MPS I patients involves allogeneic bone marrow transplantation (BMT) using a matched donor. However, therapeutic effectiveness of BMT has not yet been systematically studied in the MPS I mouse model. Our initial goal in these studies is to determine the level of wildtype donor cell engraftment needed to prevent manifestations of the disease in IDUA / recipient animals. Previously, our laboratory reported conditions for varying the level of donor cell engraftment through a combination of mild preconditioning and reduced number of donor marrow cells (Blood 2000; 96: 1334–1341). We have engrafted cohorts of 4- to 9week-old IDUA / animals with wild-type donor marrow at both high levels (90–100%) and reduced levels (10%). Donor cell engraftment levels in all animals are being assessed at regular intervals by flow cytometry. Animals are being assessed for plasma IDUA enzyme activity and urinary GAG levels as a measure of the overall degree of metabolic correction
achieved. Additionally, the animals are to be evaluated histologically to determine the effect of donor cell engraftment on the accumulation of storage materials in different tissues, and are also being subjected to neurological behavior analysis to determine the clinical effect of donor cell engraftment on the central nervous system. Results from this study will provide validation for the MPS I mouse as a model for the further development of cellular therapies in the treatment of this disease, including the development of genetic therapies involving ex vivo or in vivo transduction of autologous hematopoietic stem cells. doi:10.1016/j.ymgme.2007.10.119
108. Challenges of LSD treatment: The patient experience Durhane Wong-Rieger a, Adrian Koning b, a Canadian Organization for Rare Disorders, Toronto, Ont., Canada, b Canadian Fabry Association, Canada Therapies for lysosomal storage disorders offer tremendous hope in reducing symptoms, improving quality of life, and halting disease progression but also present significant challenges in terms of access and management. As patient groups supporting families, the Canadian Organization for Rare Disorders and the Canadian Fabry Association, with the Canadian Lysosomal Storage Disease Network, undertook a survey to understand the patient experience with these therapies. Patients and family members were recruited through patient groups, clinics, and companies. Diseases included: Gaucher’s, Fabry’s, MPS I, MPS II, MPS VI, Pompi’s, Tay-Sachs and Neiman Pick. Participants were interviewed in person or by phone using a semi-structured format. Given the relatively limited and short-term experience with these therapies, our goal was to document common and unique challenges relevant to four phases of patient experience: diagnosis, starting treatment; managing treatment, and discontinuing treatment. Patients were asked about their decision to start therapy, impact of therapy on patient and family, and concerns about long-term outcomes that affect staying on therapy. There were common patterns of response across the various diseases. Key factors influencing the starting experience were: eligibility for clinical trials or compassionate access, age of diagnosis and disease progression, access to therapy, and relationship to physician. Among factors influencing therapy management were: proximity to clinic, perceived burden of therapy including adverse events, and availability of psycho-social support. Finally, discontinuation of therapy was a relatively uncommon and unique experience. For all phases, family support was key to management. doi:10.1016/j.ymgme.2007.10.120
109. Observed changes in behaviour with assessment and procedures in neurologically affected boys with mucopolysaccharidosis type II undergoing enzyme replacement therapy Michelle Wood, Niamh Finnegan, Ashok Vellodi, Great Ormond Street Hospital London, London, UK Introduction: Challenging behaviour is a common symptom in MPS type II with neurological symptoms. This can make assessment very difficult. Physiotherapy assessment of function and nursing procedures are a very important part of management of this condition. We have observed that boys on enzyme replacement have become much more co-operative. It is possible that enzyme replacement therapy may be contributing to this behavioural improvement. Methods: Three boys with MPS II, of similar age and disease presentation, have been closely followed from baseline assessment (pre-enzyme treatment). Assessments and procedures have been graded according to ease of interaction, co-operation, participation and tolerance of handling. Results: At baseline all three boys exhibited challenging behaviour, ranging from aggression, being difficult to direct, non-compliance with
Abstracts / Molecular Genetics and Metabolism 93 (2008) S14–S46
USA, f University of California, San Francisco, USA, g University of Copenhagen, USA, h University of Alabama at Birmingham, USA, i Mount Sinai School of Medicine, New York City, NY, USA Background: Fabry disease is an X-linked lysosomal storage disorder due to deficient activity of a-galactosidase A causing progressive accumulation of glycolipids, organ damage, and early demise. The progression of renal, cardiac, and cerebrovascular disease in affected males and females has not been well characterized. Methods: An epidemiologic chart review of 447 patients (279 males, 168 females) with untreated Fabry disease from 27 expert sites in the United States and Europe was performed. Prospectively defined study endpoints included renal, cardiac, and cerebrovascular disease progression, and/or death. Results: The mean rate of estimated GFR (eGFR) decline for males (n = 243) and females (n = 152) who did not reach end stage renal disease was 2.93 and 1.02 ml/min/1.73 m2/year, respectively. More rapid eGFR decline was noted in patients with proteinuria, baseline eGFR values <60 ml/min/1.73 m2, or hypertension. Advanced Fabry nephropathy was more prevalent and occurred earlier among males than females. Cardiac events, mainly arrhythmias, occurred in 44% of patients with available information. Stroke (10%) or transient ischemic attacks (5%) were also observed. Conclusions: Proteinuria and/or reduced eGFR at baseline, and hypertension were identified as prognostic factors associated with more rapid progression of the Fabry nephropathy, and can serve as targets for therapeutic intervention. The progression rate of Fabry nephropathy increased with advancing disease. doi:10.1016/j.ymgme.2007.10.118
107. Syngeneic bone marrow transplantation in a murine model of mucopolysaccharidosis type I Daniel A. Wolf a, Kelly M. Podetz-Pedersen a, Jennifer L. Gori a, Walter C. Low b, Chester B. Whitley c, R. Scott McIvor a, a Department of Genetics, Cell Biology, and Development, University of Minnesota-Twin Cities, Minneapolis, MN, USA, b Department of Neurosurgery, University of Minnesota-Twin Cities, USA, c Department of Pediatrics, University of Minnesota-Twin Cities, USA Mucopolysaccharidosis type I (MPS I) is an autosomal recessive inherited disease caused by deficiency of the glycosidase a-L-iduronidase (IDUA). IDUA is required for the degradation of the glycosaminoglycans (GAG) heparan sulfate and dermatan sulfate, and deficiency of the enzyme leads to lysosomal storage buildup of these substrates. Specific mutations in the IDUA gene (e.g., W402X, Q70X) lead to the most severe phenotype, Hurler syndrome. Manifestations of severe MPS I begin to develop within the first 2 years of life, including growth delay, hepatosplenomegaly, skeletal deformities, excess urinary GAG, corneal clouding, and neurological defects. Recently, IDUA-deficient mouse models of MPS I have become available, providing a setting for evaluation of therapeutic approaches for the treatment of this disease. Currently, the standard of care for severe MPS I patients involves allogeneic bone marrow transplantation (BMT) using a matched donor. However, therapeutic effectiveness of BMT has not yet been systematically studied in the MPS I mouse model. Our initial goal in these studies is to determine the level of wildtype donor cell engraftment needed to prevent manifestations of the disease in IDUA / recipient animals. Previously, our laboratory reported conditions for varying the level of donor cell engraftment through a combination of mild preconditioning and reduced number of donor marrow cells (Blood 2000; 96: 1334–1341). We have engrafted cohorts of 4- to 9week-old IDUA / animals with wild-type donor marrow at both high levels (90–100%) and reduced levels (10%). Donor cell engraftment levels in all animals are being assessed at regular intervals by flow cytometry. Animals are being assessed for plasma IDUA enzyme activity and urinary GAG levels as a measure of the overall degree of metabolic correction
achieved. Additionally, the animals are to be evaluated histologically to determine the effect of donor cell engraftment on the accumulation of storage materials in different tissues, and are also being subjected to neurological behavior analysis to determine the clinical effect of donor cell engraftment on the central nervous system. Results from this study will provide validation for the MPS I mouse as a model for the further development of cellular therapies in the treatment of this disease, including the development of genetic therapies involving ex vivo or in vivo transduction of autologous hematopoietic stem cells. doi:10.1016/j.ymgme.2007.10.119
108. Challenges of LSD treatment: The patient experience Durhane Wong-Rieger a, Adrian Koning b, a Canadian Organization for Rare Disorders, Toronto, Ont., Canada, b Canadian Fabry Association, Canada Therapies for lysosomal storage disorders offer tremendous hope in reducing symptoms, improving quality of life, and halting disease progression but also present significant challenges in terms of access and management. As patient groups supporting families, the Canadian Organization for Rare Disorders and the Canadian Fabry Association, with the Canadian Lysosomal Storage Disease Network, undertook a survey to understand the patient experience with these therapies. Patients and family members were recruited through patient groups, clinics, and companies. Diseases included: Gaucher’s, Fabry’s, MPS I, MPS II, MPS VI, Pompi’s, Tay-Sachs and Neiman Pick. Participants were interviewed in person or by phone using a semi-structured format. Given the relatively limited and short-term experience with these therapies, our goal was to document common and unique challenges relevant to four phases of patient experience: diagnosis, starting treatment; managing treatment, and discontinuing treatment. Patients were asked about their decision to start therapy, impact of therapy on patient and family, and concerns about long-term outcomes that affect staying on therapy. There were common patterns of response across the various diseases. Key factors influencing the starting experience were: eligibility for clinical trials or compassionate access, age of diagnosis and disease progression, access to therapy, and relationship to physician. Among factors influencing therapy management were: proximity to clinic, perceived burden of therapy including adverse events, and availability of psycho-social support. Finally, discontinuation of therapy was a relatively uncommon and unique experience. For all phases, family support was key to management. doi:10.1016/j.ymgme.2007.10.120
109. Observed changes in behaviour with assessment and procedures in neurologically affected boys with mucopolysaccharidosis type II undergoing enzyme replacement therapy Michelle Wood, Niamh Finnegan, Ashok Vellodi, Great Ormond Street Hospital London, London, UK Introduction: Challenging behaviour is a common symptom in MPS type II with neurological symptoms. This can make assessment very difficult. Physiotherapy assessment of function and nursing procedures are a very important part of management of this condition. We have observed that boys on enzyme replacement have become much more co-operative. It is possible that enzyme replacement therapy may be contributing to this behavioural improvement. Methods: Three boys with MPS II, of similar age and disease presentation, have been closely followed from baseline assessment (pre-enzyme treatment). Assessments and procedures have been graded according to ease of interaction, co-operation, participation and tolerance of handling. Results: At baseline all three boys exhibited challenging behaviour, ranging from aggression, being difficult to direct, non-compliance with