Abstract
Background:
Intrathecal (IT) enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) has been studied to treat glycosaminoglycan storage in the central nervous system of mucopolysaccharidosis (MPS) I dogs and is currently being studied in MPS I patients.
Methods:
We studied the immune response to IT rhIDU in MPS I subjects with spinal cord compression who had been previously treated with intravenous rhIDU. We measured the concentrations of specific antibodies and cytokines in serum and cerebrospinal fluid (CSF) collected before monthly IT rhIDU infusions and compared the serologic findings with clinical adverse event (AE) reports to establish temporal correlations with clinical symptoms.
Results:
Five MPS I subjects participating in IT rhIDU trials were studied. One subject with symptomatic spinal cord compression had evidence of an inflammatory response with CSF leukocytosis, elevated interleukin-5, and elevated immunoglobulin G. This subject also complained of lower back pain and buttock paresthesias temporally correlated with serologic abnormalities. Clinical symptoms were managed with oral medication, and serologic abnormalities were resolved, although this subject withdrew from the trial to have spinal decompressive surgery.
Conclusion:
IT rhIDU was generally well tolerated in the subjects studied, although one subject had moderate to severe clinical symptoms and serologic abnormalities consistent with an immune response.
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References
Neufeld EF, Meunzer J . The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York: McGraw-Hill, 2001:3421–52.
Wraith JE . Mucopolysaccharidoses and oligosaccharidoses. In: Saudubray J-M, van den Berghe G, Walter JH, eds. Inborn Metabolic Diseases: Diagnosis and Treatment, 5th ed. Berlin: Springer-Verlag, 2012:579–90.
Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in mucopolysaccharidosis I. N Engl J Med 2001;344:182–8.
Wraith JE, Clarke LA, Beck M, et al. Enzyme replacement therapy for mucopolysaccharidosis I: a randomized, double-blinded, placebo-controlled, multinational study of recombinant human alpha-L-iduronidase (laronidase). J Pediatr 2004;144:581–8.
Enns GM, Huhn SL . Central nervous system therapy for lysosomal storage disorders. Neurosurg Focus 2008;24:E12.
Kachur E, Del Maestro R . Mucopolysaccharidoses and spinal cord compression: case report and review of the literature with implications of bone marrow transplantation. Neurosurgery 2000;47:223–8; discussion 228–9.
Dickson PI, Chen AH . Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients. Curr Pharm Biotechnol 2011;12:946–55.
Kennedy P, Swash M, Dean MF . Cervical cord compression in mucopolysaccharidosis. Dev Med Child Neurol 1973;15:194–9.
Kaufman HH, Rosenberg HS, Scott CI, Lee YY, Pruessner JL, Butler IJ . Cervical myelopathy due to dural compression in mucopolysaccharidosis. Surg Neurol 1982;17:404–10.
Lee WC, Tsoi YK, Troendle FJ, et al. Single-dose intracerebroventricular administration of galactocerebrosidase improves survival in a mouse model of globoid cell leukodystrophy. FASEB J 2007;21:2520–7.
Dodge JC, Clarke J, Treleaven CM, et al. Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-Pick A disease. Exp Neurol 2009;215:349–57.
Chang M, Cooper JD, Sleat DE, et al. Intraventricular enzyme replacement improves disease phenotypes in a mouse model of late infantile neuronal ceroid lipofuscinosis. Mol Ther 2008;16:649–56.
Hemsley KM, King B, Hopwood JJ . Injection of recombinant human sulfamidase into the CSF via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313–28.
Auclair D, Finnie J, Walkley SU, et al. Intrathecal recombinant human 4-sulfatase reduces accumulation of glycosaminoglycans in dura of mucopolysaccharidosis VI cats. Pediatr Res 2012;71:39–45.
Kakkis E, McEntee M, Vogler C, et al. Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I. Mol Genet Metab 2004;83:163–74.
Dickson P, McEntee M, Vogler C, et al. Intrathecal enzyme replacement therapy: successful treatment of brain disease via the cerebrospinal fluid. Mol Genet Metab 2007;91:61–8.
Dickson PI, Ellinwood NM, Brown JR, et al. Specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis I. Mol Genet Metab 2012;106:68–72.
Wang J, Lozier J, Johnson G, et al. Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment. Nat Biotechnol 2008;26:901–8.
Dickson P, Peinovich M, McEntee M, et al. Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I. J Clin Invest 2008;118:2868–76.
Janeway CA, Travers P, Walport M, Shlomchik MJ, eds. Immunobiology: The Immune System in Health and Disease, 6th ed. New York: Garland, 2005:347–51.
Bromberg JE, Doorduijn JK, Baars JW, van Imhoff GW, Enting R, van den Bent MJ . Acute painful lumbosacral paresthesia after intrathecal rituximab. J Neurol 2012;259:559–61.
Moris G, Garcia-Monco JC . The challenge of drug-induced aseptic meningitis. Arch Intern Med 1999;159:1185–94.
Kepa L, Oczko-Grzesik B, Stolarz W, Sobala-Szczygiel B . Drug-induced aseptic meningitis in suspected central nervous system infections. J Clin Neurosci 2005;12:562–4.
Schuchman EH, Desnick RJ . Mucopolysaccharidosis type I subtypes. Presence of immunologically cross-reactive material and in vitro enhancement of the residual alpha-L-iduronidase activities. J Clin Invest 1988;81:98–105.
Greenfield JG . Original Papers: on Froin’s syndrome, and its relation to allied conditions in the cerebrospinal fluid. J Neurol Psychopathol 1921;2:105–41.
Mirza S, Adams WM, Corkhill RA . Froin’s syndrome revisited, 100 years on. Pseudo-Froin’s syndrome on MRI. Clin Radiol 2008;63:600–4.
Asano T, Ichiki K, Koizumi S, et al. Enhanced expression of cytokines/chemokines in cerebrospinal fluids in mumps meningitis in children. Pediatr Int 2011;53:143–6.
John CC, Panoskaltsis-Mortari A, Opoka RO, et al. Cerebrospinal fluid cytokine levels and cognitive impairment in cerebral malaria. Am J Trop Med Hyg 2008;78:198–205.
Ichiyama T, Ito Y, Kubota M, Yamazaki T, Nakamura K, Furukawa S . Serum and cerebrospinal fluid levels of cytokines in acute encephalopathy associated with human herpesvirus-6 infection. Brain Dev 2009;31:731–8.
Pinto Junior VL, Rebelo MC, Gomes RN, Assis EF, Castro-Faria-Neto HC, Bóia MN . IL-6 and IL-8 in cerebrospinal fluid from patients with aseptic meningitis and bacterial meningitis: their potential role as a marker for differential diagnosis. Braz J Infect Dis 2011;15:156–8.
Maimone D, Gregory S, Arnason BG, Reder AT . Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol 1991;32:67–74.
Trysberg E, Carlsten H, Tarkowski A . Intrathecal cytokines in systemic lupus erythematosus with central nervous system involvement. Lupus 2000;9:498–503.
Mogi M, Harada M, Narabayashi H, Inagaki H, Minami M, Nagatsu T . Interleukin (IL)-1 beta, IL-2, IL-4, IL-6 and transforming growth factor-alpha levels are elevated in ventricular cerebrospinal fluid in juvenile parkinsonism and Parkinson’s disease. Neurosci Lett 1996;211:13–6.
Mittleman BB, Castellanos FX, Jacobsen LK, Rapoport JL, Swedo SE, Shearer GM . Cerebrospinal fluid cytokines in pediatric neuropsychiatric disease. J Immunol 1997;159:2994–9.
Ludwig J, Binder A, Steinmann J, Wasner G, Baron R . Cytokine expression in serum and cerebrospinal fluid in non-inflammatory polyneuropathies. J Neurol Neurosurg Psychiatr 2008;79:1268–73.
Kakkis E, Lester T, Yang R, et al. Successful induction of immune tolerance to enzyme replacement therapy in canine mucopolysaccharidosis I. Proc Natl Acad Sci USA 2004;101:829–34.
Kakkis ED, McEntee MF, Schmidtchen A, et al. Long-term and high-dose trials of enzyme replacement therapy in the canine model of mucopolysaccharidosis I. Biochem Mol Med 1996;58:156–67.
Tschudy MM, Arcara KM, eds. Johns Hopkins: The Harriet Lane Handbook, 19th ed. Philadelphia: Mosby, 2012.
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Vera, M., Le, S., Kan, Sh. et al. Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients. Pediatr Res 74, 712–720 (2013). https://doi.org/10.1038/pr.2013.158
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DOI: https://doi.org/10.1038/pr.2013.158
