TY - JOUR
T1 - Intrathecal enzyme replacement therapy improves motor function and survival in a preclinical mouse model of infantile neuronal ceroid lipofuscinosis
AU - Lu, Jui Yun
AU - Nelvagal, Hemanth R.
AU - Wang, Lingling
AU - Birnbaum, Shari G.
AU - Cooper, Jonathan D.
AU - Hofmann, Sandra L.
N1 - Funding Information:
The authors wish to thank Drs. Peter Lobel and David Sleat for advice in the experimental design, Dr. James Richardson and John Shelton of the UT Southwestern Molecular Pathology Core for PPT1 immunostaining and microscopy, and Lauren Peca for performing the behavioral tests. This work was funded by Taylor's Tale , the Batten Disease Support and Research Association , the Batten Disease Family Association , and a King's College London Graduate School International Studentship award to HRN.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - The neuronal ceroid lipofuscinoses (NCLs) are a group of related hereditary lysosomal storage disorders characterized by progressive loss of neurons in the central nervous system resulting in dementia, loss of motor skills, seizures and blindness. A characteristic intralysosomal accumulation of autofluorescent storage material occurs in the brain and other tissues. Three major forms and nearly a dozen minor forms of NCL are recognized. Infantile-onset NCL (CLN1 disease) is caused by severe deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1) and no therapy beyond supportive care is available. Homozygous Ppt1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5. months of age and death around 8. months. Direct delivery of lysosomal enzymes to the cerebrospinal fluid is an approach that has gained traction in small and large animal models of several other neuropathic lysosomal storage diseases, and has advanced to clinical trials. In the current study, Ppt1 knockout mice were treated with purified recombinant human PPT1 enzyme delivered to the lumbar intrathecal space on each of three consecutive days at 6. weeks of age. Untreated PPT1 knockout mice and wild-type mice served as additional controls. Four enzyme concentration levels (0, 2.6, 5.3 and 10.6. mg/ml of specific activity 20. U/mg) were administered in a volume of 80. μl infused over 8. min. Each group consisted of 16-20 mice. The treatment was well tolerated. Disease-specific survival was 233, 267, 272, and 284. days for each of the four treatment groups, respectively, and the effect of treatment was highly significant (p<0.0001). The timing of motor deterioration was also delayed. Neuropathology was improved as evidenced by decreased autofluorescent storage material in the spinal cord and a decrease in CD68 staining in the cortex and spinal cord. The improvements in motor function and survival are similar to results reported for preclinical studies involving other lysosomal storage disorders, such as CLN2/TPP1 deficiency, for which intraventricular ERT is being offered in clinical trials. If ERT delivery to the CSF proves to be efficacious in these disorders, PPT1 deficiency may also be amenable to this approach.
AB - The neuronal ceroid lipofuscinoses (NCLs) are a group of related hereditary lysosomal storage disorders characterized by progressive loss of neurons in the central nervous system resulting in dementia, loss of motor skills, seizures and blindness. A characteristic intralysosomal accumulation of autofluorescent storage material occurs in the brain and other tissues. Three major forms and nearly a dozen minor forms of NCL are recognized. Infantile-onset NCL (CLN1 disease) is caused by severe deficiency in a soluble lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1) and no therapy beyond supportive care is available. Homozygous Ppt1 knockout mice reproduce the known features of the disease, developing signs of motor dysfunction at 5. months of age and death around 8. months. Direct delivery of lysosomal enzymes to the cerebrospinal fluid is an approach that has gained traction in small and large animal models of several other neuropathic lysosomal storage diseases, and has advanced to clinical trials. In the current study, Ppt1 knockout mice were treated with purified recombinant human PPT1 enzyme delivered to the lumbar intrathecal space on each of three consecutive days at 6. weeks of age. Untreated PPT1 knockout mice and wild-type mice served as additional controls. Four enzyme concentration levels (0, 2.6, 5.3 and 10.6. mg/ml of specific activity 20. U/mg) were administered in a volume of 80. μl infused over 8. min. Each group consisted of 16-20 mice. The treatment was well tolerated. Disease-specific survival was 233, 267, 272, and 284. days for each of the four treatment groups, respectively, and the effect of treatment was highly significant (p<0.0001). The timing of motor deterioration was also delayed. Neuropathology was improved as evidenced by decreased autofluorescent storage material in the spinal cord and a decrease in CD68 staining in the cortex and spinal cord. The improvements in motor function and survival are similar to results reported for preclinical studies involving other lysosomal storage disorders, such as CLN2/TPP1 deficiency, for which intraventricular ERT is being offered in clinical trials. If ERT delivery to the CSF proves to be efficacious in these disorders, PPT1 deficiency may also be amenable to this approach.
KW - Batten disease
KW - Enzyme replacement therapy
KW - Infantile neuronal ceroid lipofuscinosis
KW - Lysosomal storage disorder
KW - Palmitoyl protein thioesterase
UR - http://www.scopus.com/inward/record.url?scp=84940897379&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2015.05.005
DO - 10.1016/j.ymgme.2015.05.005
M3 - Article
C2 - 25982063
AN - SCOPUS:84940897379
SN - 1096-7192
VL - 116
SP - 98
EP - 105
JO - Molecular genetics and metabolism
JF - Molecular genetics and metabolism
IS - 1-2
ER -