Recent trials in patients with neurodegenerative diseases documented the safety of gene therapy based on adeno-associated virus (AAV) vectors deposited into the brain. Inborn errors of the metabolism are the most frequent causes of neurodegeneration in pre-adulthood. In Sanfilippo syndrome, a lysosomal storage disease in which heparan sulfate oligosaccharides accumulate, the onset of clinical manifestation is before 5 years. Studies in the mouse model showed that gene therapy providing the missing enzyme α-N-acetyl-glucosaminidase to brain cells prevents neurodegeneration and improves behavior. We now document safety and efficacy in affected dogs. Animals received eight deposits of a serotype 5 AAV vector, including vector prepared in insect Sf9 cells. As shown previously in dogs with the closely related Hurler syndrome, immunosuppression was necessary to prevent neuroinflammation and elimination of transduced cells. In immunosuppressed dogs, vector was efficiently delivered throughout the brain, induced α-N-acetyl-glucosaminidase production, cleared stored compounds and storage lesions. The suitability of the procedure for clinical application was further assessed in Hurler dogs, providing information on reproducibility, tolerance, appropriate vector type and dosage, and optimal age for treatment in a total number of 25 treated dogs. Results strongly support projects of human trials aimed at assessing this treatment in Sanfilippo syndrome.

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disease caused by loss of activity of α-L-iduronidase and attendant accumulation of the glycosaminoglycans dermatan and heparan sulfates. Current treatments are suboptimal and leave residual disease including corneal clouding, skeletal deformities, valvular heart disease and cognitive impairment. We treated neonatal mucopolysaccharidosis I dogs with intravenous recombinant α-L-iduronidase replacement therapy at the conventional 0.58 mg/kg or a higher 1.57 mg/kg weekly dose for 65-81 weeks. In contrast to previous results in animals and patients treated at a later age, all animals failed to mount an antibody response to enzyme therapy, consistent with neonatal tolerization. The higher dose of enzyme led to complete normalization of lysosomal storage in liver, spleen, lung, kidney, synovium and myocardium, as well as in the hard-to-treat mitral valve. Cardiac biochemistry and Author contributions: NME and PID conceived and designed the study, analyzed data and wrote the manuscript. ADD performed experiments and data analysis and wrote the manuscript. MFM, CAV, and AF-W performed pathology. CHV, WG, and EAR performed radiology and MRIs. MP, SS, AHC and SL performed biochemistry. JKJ and EMS conducted animal work. KLK, JDP, and JAW conducted veterinary neurology procedures and support. WAW and LEM conducted veterinary cardiology procedures and support. RDW, DMB and AMB conducted veterinary ophthalmology procedures and support.Publisher's Disclaimer: 'This manuscript has been accepted for publication in Science Translational Medicine. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencetranslationalmedicine.org.The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.' natural history study to measure intellectual function over time in these patients is ongoing. In the canine model, even a larger 2 mg/kg weekly dose of ERT was not sufficient to clear accumulated GAG from the heart valve in older animals, though it was able to improve histologic evidence of lysosomal storage efficacy(12,13). It is possible that some MPS I pathology, including valvular disease, may be difficult or impossible to reverse. NIH Public AccessWhile some MPS I disease is not readily reversed by IV ERT, prevention may be easier to achieve. In particular, we were intrigued by reports that early or high-dose IV ERT could treat lysosomal storage in the brain in mice (14-20). We therefore treated MPS I dogs shortly after birth to determine whether hard-to-treat disease including cardiac valvular disease, skeletal disease, and corneal clouding, would respond to early initiation of therapy, and whether treating them would require a higher dose. We also sought to compare early, high-dose IV ERT to ERT administered directly into spinal fluid (intrathecally, IT) (21,22) for treatment of lysosomal storage in ...

A 15-month-old cat presented for evaluation of worsening generalized proprioceptive ataxia. Computed tomography of the cervical spine revealed the presence of a compressive extradural bony mass involving the dorsal aspect of C1. Surgical exploration and debulking of the mass was performed. Histological evaluation of the mass revealed fibrovascular tissue consistent with a vascular hamartoma. This mass was deemed to be originating from the soft tissue associated with the C1 vertebra with subsequent bony proliferation. Surgical debulking of the mass resulted in complete resolution of clinical signs with no evidence of recurrence 2 years after surgery.

Abstract. A 6-month-old, female, intact Rottweiler dog was presented to the Iowa State University Veterinary Teaching Hospital for a progressive history of abnormal behavior and generalized ataxia. At necropsy, there was eosinophilic infiltration of the brain and spinal cord, most severe in the medulla oblongata, cerebellum, and cervical spinal cord. Infiltrates of eosinophils were also present in the liver and small intestines. The dog was diagnosed with idiopathic eosinophilic meningoencephalomyelitis based on cerebrospinal fluid analysis, histopathology, and special stains to exclude etiologic agents.Key words: Eosinophil; meningitis; meningoencephalomyelitis; Rottweilers.Eosinophilic meningoencephalitis is a rare condition in veterinary medicine; the etiology in the majority of canine cases is often undetermined. Protozoan and nematode parasites can occasionally cause eosinophilic encephalitis in dogs.5 In humans, the most common cause of eosinophilic meningitis is a result of infection with a rat lungworm (Angiostrongylus cantonensis). This infection is usually nonfatal and occurs after ingesting third-stage larvae of the lungworm in contaminated produce or inadequately cooked snails. 7 In the past 2 decades, there have been several reports of an idiopathic form of eosinophilic meningitis that has been shown to affect dogs, cats, and cattle. [1][2][3]6,[8][9][10] In these cases, no infectious etiology has been identified; however, Rottweiler and Golden Retriever dogs appear to be overrepresented, indicating a possible breed predisposition. Dogs with eosinophilic meningoencephalitis often have signs consistent with both brain and spinal cord disease; however, no report has histologically documented the spinal cord changes. In the current report, a young Rottweiler dog with an acute onset of a severe and fatal eosinophilic meningoencephalomyelitis is described.A 6-month-old, 20 kg, female, intact Rottweiler presented to the referring veterinarian with a 6-day history of mild ataxia, lethargy, and decreased appetite. Blood work was performed, including complete blood cell count (CBC) and biochemical profile. The following abnormalities were noted: hypercholesterolemia (328 mg/dl, reference interval: 125-260 mg/dl) and moderate eosinophilia (4,200/ml, reference interval: 0-600/ml). A urinalysis was also performed, which revealed the presence of white blood cells, red blood cells, and bacteria in the sediment. The dog was given clindamycin (300 mg orally, every 12 hr), kept for a few hours for observation, and then sent home. The following day, the dog presented to Iowa State University Veterinary Teaching Hospital (ISU-VTH, Ames, Iowa) with worsening tetraparesis and proprioceptive ataxia.On presentation to the ISU-VTH, the dog was in lateral recumbency, but was quiet, alert, and responsive. On physical examination, the dog had a heart rate of 100 beats per min, a rectal temperature of 40.6uC, and was panting. Generalized muscle tremors were present along with apparent hypersensitivity to touch and sound. On ne...

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