Efficacy of phosphodiesterase-4 inhibitors in juvenile Batten disease (CLN3).
Juvenile neuronal ceroid lipofuscinosis (JNCL), or juvenile Batten disease, is a pediatric lysosomal storage disease caused by autosomal recessive mutations in CLN3, typified by blindness, seizures, progressive cognitive and motor decline, and premature death. Currently, there is no treatment for JNCL that slows disease progression, which highlights the need to explore novel strategies to extend the survival and quality of life of afflicted children. Cyclic adenosine monophosphate (cAMP) is a second messenger with pleiotropic effects, including regulating neuroinflammation and neuronal survival. Here we investigated whether 3 phosphodiesterase-4 (PDE4) inhibitors (rolipram, roflumilast, and PF-06266047) could mitigate behavioral deficits and cell-specific pathology in the Cln3Δex7/8mouse model of JNCL.



In a randomized, blinded study, wild-type (WT) and Cln3Δex7/8mice received PDE4 inhibitors daily beginning at 1 or 3 months of age and continuing for 6 to 9 months, with motor deficits assessed by accelerating rotarod testing. The effect of PDE4 inhibitors on cAMP levels, astrocyte and microglial activation (glial fibrillary acidic protein and CD68, respectively), lysosomal pathology (lysosomal-associated membrane protein 1), and astrocyte glutamate transporter expression (glutamate/aspartate transporter) were also examined in WT and Cln3Δex7/8animals.



cAMP levels were significantly reduced in the Cln3Δex7/8brain, and were restored by PF-06266047. PDE4 inhibitors significantly improved motor function in Cln3Δex7/8mice, attenuated glial activation and lysosomal pathology, and restored glutamate transporter expression to levels observed in WT animals, with no evidence of toxicity as revealed by blood chemistry analysis.



These studies reveal neuroprotective effects for PDE4 inhibitors in Cln3Δex7/8mice and support their therapeutic potential in JNCL patients. Ann Neurol 2016;80:909-923.
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
Amy
A
Aldrich
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE.
Megan E
ME
Bosch
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
Rachel
R
Fallet
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
Jessica
J
Odvody
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
Maria
M
Burkovetskaya
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
Kakulavarapu V
KV
Rama Rao
Department of Basic & Clinical Neuroscience, King's College, London, United Kingdom.|Los Angeles Biomedical Research Institute and David Geffen School of Medicine at UCLA, Harbor UCLA Medical Center, Torrance, CA.
Jonathan D
JD
Cooper
Department of Ophthalmology and Visual Sciences, University of Iowa Carver College of Medicine, Iowa City, IA.
Arlene V
AV
Drack
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE.
Tammy
T
Kielian
D027322:Amino Acid Transport System X-AG / Q000096:biosynthesis; D000631:Aminopyridines / Q000627:therapeutic use; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001549:Benzamides / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003521:Cyclopropanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics; D009048:Motor Skills / Q000187:drug effects; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000235:genetics; D018696:Neuroprotective Agents / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D020889:Rolipram / Q000627:therapeutic use; D045442:Rotarod Performance Test; D000097382:CD68 Molecule
D027322:Amino Acid Transport System X-AG; D000631:Aminopyridines; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001549:Benzamides; D000242:Cyclic AMP; D003521:Cyclopropanes; D005904:Glial Fibrillary Acidic Protein; D052118:Lysosomal-Associated Membrane Protein 1; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D018696:Neuroprotective Agents; D058988:Phosphodiesterase 4 Inhibitors; D020889:Rolipram; C081026:CD68 protein, mouse; D000097382:CD68 Molecule; C102229:CLN3 protein, mouse; C424423:Roflumilast