Genes, Mutations and Gene Therapy

ABCR in STGD and RP

Stargardt disease (STGD) is caused by hypomorphic mutations in ABCR, whereas truncating mutations are associated with retinitis pigmentosa (RP). Shroyer et al. (p. 2757) report a family that manifests both STGD and RP wherein all affected individuals are compound heterozygous for missense mutations. A complex allele consisting of two missense changes on a single chromosome segregates with both STGD and RP. Biochemical analysis of the complex allele reveals defects that are greater than a simple additive effect of the individual mutations. This synergism may occur for other complex ABCR alleles, and suggests potential modification of mutant alleles by polymorphisms or other “benign” alterations on the same chromosome. 

M1S1 and Corneal Dystrophy

A new mutation was found in M1S1 gene causing gelatinous drop-like corneal dystrophy, a form of primary amyloidosis of the cornea leading to blindness. For the first time, Tasa et al. (p. 2762) performed mutation analysis in a Caucasian family suffering from drop-like corneal dystrophy. Also a common polymorphism was found very close to the mutation which must be considered while designing molecular analysis method for mutation detection. One can speculate that the mutation could also be found in other patients among European descendants. 

Corneal Antisense Petides

This study by Haddox et al. (p. 2769) represents the first use of an antisense peptide, RTR tetramer, as a therapeutic agent to treat eye disease. The concept of designing RTR tetramer to inactivate the neutrophil chemoattractants, Ac-PGP and Me-PGP, is a novel approach to this disastrous injury. The therapeutic in vivo result observed with this lead compound justifies the continuation of an iterative process in the development of more potent antisense peptides. This study should therefore be interpreted as a first step in the development of an entirely new class of inhibitors in the treatment of the alkali-injured eye. 

Glaucoma Gene Therapy

Kee et al. (p. 2856) pave the way for gene therapy as a treatment for glaucoma. Stromelysin, which is a member of the matrix metalloproteinases, degrades the trabecular proteoglycans, which are the putative outflow resistance source, and thereby increases the outflow facility. Kee et al. constructed the adenoviral vector containing stromelysin cDNA, a candidate therapeutic gene for glaucoma, and observed the expression of stromelysin in trabecular cells as well as in the rat trabecular meshwork in vivo. This study raises the possibility that in vivo introduction of the stromelysin gene into the trabecular meshwork could potentially be a viable approach to the treatment of glaucoma. 

Dominant Cataract Mutation

During an ethylnitrosourea mutagenesis screen a novel mouse mutant was found (Aey7), which is characterized by a nuclear opacity and zonular cataract. The mutation was mapped to chromosome 17 making the αA-crystallin encoding gene (Cryaa) to an excellent candidate. As reported in Graw et al. (p. 2909), sequence analysis revealed a mutation of T to A at pos. 371 in the Cryaa cDNA leading to an exchange of Val for Glu at codon 147 affecting the C-terminal region of theα A-crystallin. The Aey7 mutant represents the first dominant mouse cataract mutation affecting the Cryaa gene. Compared to the β- and γ-crystallin encoding genes, mutations in the α-crystallin encoding genes are rare. 

Mitochondrial DNA Damage

Mitochondrial dysfunction is increasingly recognized as a feature of aging post-mitotic tissues, contributing to decreased function and cell loss. The retina is composed of such tissue-elements and has very high oxidative metabolism. Barron et al. (p. 3016) show both an age-related accumulation of mitochondrial DNA damage in the photoreceptor layer of the human retina and a similar increase in the number of cones showing a histochemical absence of cytochrome c oxidase (a mitochondria-specific enzyme) activity. Both abnormalities are more prevalent in the macula than elsewhere in the retina. This, and the observation of high levels of mutant in the photoreceptor layer from a donor with age-related maculopathy (ARM), suggests a role for mitochondria in retinal aging and age-related pathology. 

Rpe65 Gene and Lipofuscin

Lipofuscin accumulation in the retinal pigment epithelium (RPE) has been implicated in the pathology associated with age-related macular degeneration. Thus, it is important to develop a detailed understanding of the mechanisms that underlie RPE lipofuscin formation. Substantial evidence indicates that visual cycle retinoids play key roles in generating this pigment. Lack of functional RPE65 protein prevents conversion of vitamin A to visual cycle retinoids. Katz and Redmond (p. 3023) demonstrated that an Rpe65 gene defect blocks RPE lipofuscin accumulation. This indicates that unless retinoids traverse the visual cycle, RPE lipofuscin will not form. 

Diabetes Gene Expression

Whereas previous studies have assigned a pathogenic role to specific molecules, a coordinated large-scale investigation of gene expression in the diabetic retina has not yet been reported. In the current study by Joussen et al. (p. 3047), the retinal expression of 5147 genes was studied in diabetic and non-diabetic animals with cDNA microarrays. Consistent with recent data, the expression profile observed in early diabetes suggests an underlying retinal inflammatory process. The genome wide approach utilized in this study should help speed the identification of therapeutic drug targets and markers for disease monitoring.