Research
Feline rod cone retinal degeneration; a disease comparable to human Retinitis Pigmentosa
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Figure 1A. Cat globe with early stage rod-cone degeneration.
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A hereditary retinal disease was discovered in the Abyssinian strain of cats and
further described by Dr. Narfström, in Sweden more than 20 years ago. Using clinical
and laboratory methods, the disease was found to affect the visual cells; solitary
rods were found primarily to degenerate. There was a slow progression of the disease
but ultimately there was a complete photoreceptor cell loss resulting in blindness.
Thus, this disease is very similar to human Retinitis Pigmentosa (RP), a blinding
disease that affects 1 person in 3500 on a world-wide basis. The specific gene defect
in the feline counterpart has not yet been found but research is in progress, in
collaboration with the National Cancer Institute, Frederick, MD. Affected cats are
used for various studies in worldwide collaborative projects, such as studies on
retinal circulation, oxygenation and metabolism in the disease process, and retinal
electrophysiology. Treatment studies include transplantation of donor feline tissue
and intraocular deposition of stem cells. Electron microscopic and immunocytochemical
studies are essential techniques used in order to evaluate host-graft interaction
and cellular connectivity in this research.
Canine RPE65 null mutation; a disease comparable to human Leber’s Congenital Amaurosis
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Figure 1B. Cat globe with late-stage rod-cone degeneration.
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A hereditary retinal disease, similar to human Leber’s congenital amaurosis, was
discovered by Dr. Narfström in a strain of Briard dogs and further described in
collaboration with researchers in Sweden and Germany approximately 15 years ago.
The disorder results from an RPE65 null mutation causing congenital severe visual
impairment or blindness due to a base-pair deletion and lack of formation of 11-cis
retinal in the outer retina. As one of two groups in the world working with the
dog model on this disorder, gene replacement therapy was performed by Dr. Narfström
and her collaborators at the University of Missouri-Columbia, using subretinal injections
of an rAAV.RPE65 gene construct. These surgeries, initiated 2001, have shown remarkable
improvement of visual function in affected dogs, demonstrated by objective behavioral
and electrophysiological testing after treatment. Long-term studies of groups of
gene transfer treated dogs are presently directed towards further functional and
structural analysis of their retinas. Function is assessed by both objective behavioral
testing and electrophysiologic studies. Structure is evaluated by in vivo imaging
of the retina using funduscopy and angiography. Further studies are performed using
immunohisto-chemistry, light and electron microscopy of retinal tissue. The goal
of these specific studies is to elucidate if there is long-term saving of photoreceptors
after gene transfer or if the visual cells continue to degenerate. Also the safety
of the subretinal injections is studied in the treated dogs in order to prepare
for human clinical trials.
Canine ceroid-lipofuscinosis; a disease comparable to human Batten’s disease
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Figure 2. Gene transfer in progress: the construct (rAAV.RPE65) is injected subretinally.
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The ceroid-lipofuscinosis (CL) are a group of neurodegenerative diseases that primarily
affect the neuronal cells and that share many clinical and pathological features
in animals and humans. Over the past 10 years, Professor Narfström has been involved
in studies of CL in the Polish Owczarek Nizziny (PON) dog in northern Europe. At
her Missouri lab she is now continuing her clinical studies of CL also in the Tibetan
Terrier dog breed in collaboration with Doctors Gary Johnson, Dennis O’Brien, and
Martin Katz. The latter group have been involved in CL research also for many years
and have recently found and described the mutation responsible for the disorder
in the English Setter. With the canine genome now described and several candidate
genes available, research into the gene defect is in progress for the PON dog as
well as for other dog breeds, with the aim of developing therapies for these neurological
and also, in many cases, blinding disorders.
Full-field electroretinography (ERG) in large animals
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Figure 3. Electroretinography (ERG) in preparation. The dog is under general anesthesia.
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One of Dr. Narfström’s main interests is retinal electrophysiology. She has been
involved in electroretinographic (ERG) studies using large animals (mainly dogs
and cats) for over 2 decades. When she was President of the European College of
Veterinary Ophthalmology (ECVO) she initiated an international group for “harmonization
of ERG techniques” used in dogs, which resulted in guidelines for performing canine
ERGs, published in Documenta Ophthalmologica, 2002, the official journal of the
International Society for Clinical Electrophysiology of Vision (ISCEV). Over the
past years, Dr. Narfström has been working specifically on the early diagnosis of
hereditary retinal disease, utilizing ERG recordings, well before retinal changes
are obvious by ophthalmoscopy.
Publications
Narfström K. Hereditary progressive retinal atrophy in the Abyssinian cat. J Hered
74:273-276, 1983.
Narfström K. Progressive retinal atrophy in the Abyssinian cat: Clinical characteristics.
Invest Ophthalmol Vis Sci 26:193-200, 1985.
Narfström K, Nilsson SE, Andersson, BE. Progressive retinal atrophy in the Abyssinian
cat. Studies of the DC-recorded electroretinogram and the standing potential of
the eye. Br J Ophthalmol 69:618-623, 1985.
Narfström K, Nilsson SE. Progressive retinal atrophy in the Abyssinian cat: Electron
microscopy. Invest Ophthalmol Vis Sci 27:1569, 1986.
Ekström P, Sanyal S, Narfström K, Chader J, Van Veen T. Accumulation of glial fibrillary
acidic protein in Muller radial glia during retina degeneration. Invest Ophthalmol
Vis Sci 29:1363-1371, 1988.
Narfström K, Arden GB, Nilsson SE. Retinal sensitivity in hereditary retinal degeneration
in Abyssinian cats: Electrophysiological similarities between human and cat. Br
J Ophthalmol 73:516-521, 1989.
Narfström K, Nilsson SE, Wiggert B, Lee L, Chader J, Van Veen T. Reduced IRBP level,
a possible cause for retinal degeneration in the Abyssinian cat. Cell Tissue Res
257:631-639, 1989.
Narfström K, Wrigstad A, Nilsson SE. The Briard dog: A new animal model for congenital
stationary night blindness. Br J Ophthalmol 73:750-756, 1989.
Nilsson SE, Wrigstad A, Narfström K. Changes in the DC electroretinogram in Briard
dogs with hereditary congenital night blindness and partial day blindness. Exp Eye
Res 53:415-417, 1991.
Wrigstad A, Nilsson SE, Narfström K. Ultrastructural changes of the retina in Briard
dogs with hereditary congenital night blindness and partial day blindness. Exp Eye
Res 55:805-818, 1992.
Narfström K, Ivert L, Yamamoto S, Gouras P. Adaptation of rod and cone electroretinograms
in the Abyssinian cat hereditary rod cone degeneration. Clin Vision Sci 8:177-185,
1993.
Narfström K, Wrigstad A, Ekesten B, Nilsson SE. Hereditary retinal dystrophy in
the Briard dog: Clinical and hereditary characteristics. Prog Vet Comp Ophthalmol
4:85-92, 1994.
Narfström K, Andersson BE, Andreasson S, Gouras P. Clinical electroretinography
in the dog using Ganzfeld stimulation: A practical method of examining rod and cone
function. Doc Ophthalmol 90:279-290, 1995.
Andersson RE, Maude MB, Narfström K, Nilsson SE. Lipids of plasma, retina and retinal
pigment epithelium in Swedish Briard dogs with a slowly progressive retinal degeneration.
Exp Eye Res 64:181-187, 1996.
Veske A, Narfström K, Finckh U, Sargan DR, Nilsson SE, Gal A. Isolation of canine
retinal arrestin cDNA and exclusion of three candidate genes for the Swedish Briard
retinal dystrophy. Curr Eye Res 16:270-274, 1997.
Narfström K, Ekesten B. Electroretinographic evaluation of Papillon dogs with and
without hereditary retinal degeneration. Am J Vet Res 59:221-226, 1998.
Ivert L, Gouras P, Naeser P, Narfström K. Photoreceptor allografts in a feline model
of retinal degeneration. Graefe´s Arch Clin Exp Ophthalmol 236:844-852, 1998.
Aguirre GD, Baldwin V, Pearce-Kelling S, Narfström K, Ray K, Acland G. Congenital
stationary night blindness in the dog: common mutation in the RPE65 gene indicates
founder effect. Mol Vis 30;4:23, 1998. (http://www.molvis.org/molvis/v4/P23/)
Veske A, Nilsson SE, Narfström K, Gal A. Retinal dystrophy of Swedish Briard/Beagle
dogs is due to a 4-base pair deletion in RPE65. Genomics 57(1):57-61, 1999.
Seeliger M, Narfström K. Functional assessment of the regional distribution of disease
in a cat model of hereditary retinal degeneration. Invest Ophthalmol Vis Sci 41:1998-2005,
2000.
Seeliger MW, Narfström K, Reinhard J, Zrenner E, Sutter E. Continuous monitoring
of the stimulated area in multifocal ERG. Doc Ophthalmol 100:167-184, 2000.
Nilsson SE, Mäepea O, Alm A, Narfström K. Ocular blood flow and retinal metabolism
in Abyssinian cats with hereditary retinal degeneration. Invest Ophthalmol Vis Sci
42:1038-1044, 2001.
Narfström K, Ehinger B, Bruun A. Immunocytochemistry of cone photoreceptors and
cells of the inner retina in feline hereditary retinal degeneration. Vet Ophthalmol
4:141-145, 2001.
Narfström K, Ekesten B, Rosolen S, Spiess B, Percicot C, Ofri R. Guidelines for
clinical electrophysiology in the dog. Doc Ophthalmol 105(2):83-92, 2002.
Narfström K. Electroretinography in veterinary medicine - Easy or accurate? J Vet
Ophthalmol 5:249-251, 2002.
Bragadottir R, Narfström K. Lens sparing pars plana vitrectomy and retinal transplantation
in cats. Vet Ophthalmol 6(2):135-9, 2003.
Narfström K, Katz M, Bragadottir R, Seeliger M, Boulanger A, Redmond M, Lai CM,
Rakoczy E. Functional and structural recovery of the retina after gene therapy in
the RPE65 null mutation dog. Invest Ophthalmol Vis Sci 44(4):1663-72, 2003.
Narfström K, Katz M, Ford M, Redmond M, Rakoczy E, Bragadottir R.In vivo gene therapy
in young and adult RPE65-/- dogs produces long-term visual improvement. J Hered
94(1):31-7, 2003.
Ford M, Bragadottir R, Rakoczy PE, Narfström K. Gene transfer in the RPE65 null
mutation dog: Relationship between construct volume, visual behavior and electroretinographic
results. Doc Ophthalmol 107(1):79-86, 2003.
Vaegan, Narfström K. Optimal discrimination of an Abyssinian cat recessive retinal
degeneration: A short electroretinogram (ERG) protocol is more efficient than a
long one. Clin Experiment Ophthalmol 32(6):619-25, 2004.
Katz M, Narfström K, Johnson GS, O’Brien DP. Assessment of retinal function and
characterization of lysosomal storage body accumulation in the retinas and brains
of Tibetan Terriers with ceroid-lipofuscinosis. Am J Vet Res 66(1):67-76, 2005.
Rah H, Maggs DJ., Blankenship TN, Narfström K, Lyons L.A. Early-onset autosomal
recessive progressive retinal atrophy in Persian cats. Accepted, Invest Ophthalmol
Vis Sci, 2005.
Selected Book Chapters
Narfström K, Ekesten B. The Canine Posterior Segment. In: Kirk N. Gelatt (ed.),
Essentials of Veterinary Ophthalmology. Lippincott Williams & Williams, Philadelphia.
Pp: 253-283. 2000.
Narfström K, Bragadottir R, Redmond TM, Rakoczy EP, Van Veen T, Bruun A. Functional
and structural evaluation after AAV.RPE65 gene transfer in the canine model of Leber’s
Congenital Amaurosis. In: Hollyfield JG, Anderson RE, LaVail MM (eds.), Retinal
Degenerations. Kluwer Academic/Plenum Publishers, New York. Pp: 423-430. 2003.
Previous and Ongoing Research Support
Swedish Medical Research Association, Foundation Fighting Blindness, National Cancer
Institute, National Institutes of Health, University of Missouri Research Council
and University of Missouri Research Board.
