Identical Mutation in a Novel Retinal Gene Causes Progressive Rod-Cone Degeneration in Dogs and Retinitis Pigmentosa in Humans

Progressive rod–cone degeneration (prcd) is a late-onset, autosomal recessive photoreceptor degeneration of dogs and a homolog for some forms of human retinitis pigmentosa (RP). Previously, the disease-relevant interval was reduced to a 106-kb region on CFA9, and a common phenotype-specific haplotype was identified in all affected dogs from several different breeds and breed varieties. Screening of a canine retinal EST library identified partial cDNAs for novel candidate genes in the disease-relevant interval. The complete cDNA of one of these, PRCD, was cloned in dog, human, and mouse. The gene codes for a 54-amino-acid (aa) protein in dog and human and a 53-aa protein in the mouse; the first 24 aa, coded for by exon 1, are highly conserved in 14 vertebrate species. A homozygous mutation (TGC → TAC) in the second codon shows complete concordance with the disorder in 18 different dog breeds/breed varieties tested. The same homozygous mutation was identified in a human patient from Bangladesh with autosomal recessive RP. Expression studies support the predominant expression of this gene in the retina, with equal expression in the retinal pigment epithelium, photoreceptor, and ganglion cell layers. This study provides strong evidence that a mutation in the novel gene PRCD is the cause of autosomal recessive retinal degeneration in both dogs and humans

Pharmacological and rAAV Gene Therapy Rescue of Visual Functions in a Blind Mouse Model of Leber Congenital Amaurosis

BACKGROUND: Leber congenital amaurosis (LCA), a heterogeneous early-onset retinal dystrophy, accounts for ~15% of inherited congenital blindness. One cause of LCA is loss of the enzyme lecithin:retinol acyl transferase (LRAT), which is required for regeneration of the visual photopigment in the retina. METHODS AND FINDINGS: An animal model of LCA, the Lrat (−/−) mouse, recapitulates clinical features of the human disease. Here, we report that two interventions—intraocular gene therapy and oral pharmacologic treatment with novel retinoid compounds—each restore retinal function to Lrat (−/−) mice. Gene therapy using intraocular injection of recombinant adeno-associated virus carrying the Lrat gene successfully restored electroretinographic responses to ~50% of wild-type levels (p < 0.05 versus wild-type and knockout controls), and pupillary light responses (PLRs) of Lrat (−/−) mice increased ~2.5 log units (p < 0.05). Pharmacological intervention with orally administered pro-drugs 9-cis-retinyl acetate and 9-cis-retinyl succinate (which chemically bypass the LRAT-catalyzed step in chromophore regeneration) also caused long-lasting restoration of retinal function in LRAT-deficient mice and increased ERG response from ~5% of wild-type levels in Lrat (−/−) mice to ~50% of wild-type levels in treated Lrat (−/−) mice (p < 0.05 versus wild-type and knockout controls). The interventions produced markedly increased levels of visual pigment from undetectable levels to 600 pmoles per eye in retinoid treated mice, and ~1,000-fold improvements in PLR and electroretinogram sensitivity. The techniques were complementary when combined. CONCLUSION: Intraocular gene therapy and pharmacologic bypass provide highly effective and complementary means for restoring retinal function in this animal model of human hereditary blindness. These complementary methods offer hope of developing treatment to restore vision in humans with certain forms of hereditary congenital blindness

What Do We Know About Our Future Selves? Essays on Sophistication and Prediction.

What people know about their future preferences and how they take this knowledge into account in their decisions are questions of primary importance in formal models of intertemporal choice and in many domains of public policy. I investigate prediction of changes in state-dependent preferences in the case of habit formation, prediction of future self-control problems, and how agents with self knowledge with respect to future self-control problems think about the actions and beliefs of their future selves.In chapter one I and a coauthor extend the gym-attendance study of Charness and Gneezy (2009) by incentivizing subjects to attend the gym for a month and observing their pre- and post-treatment attendance relative to a control group. In addition we elicit subjects' pre- and post-treatment predictions of their post-treatment attendance. We find a habit formation effect similar to that of Charness and Gneezy in the short-run, but with substantial decay caused by winter vacation. We additionally find that subjects seriously over-predict future attendance, which we interpret as evidence of partial naivete with respect to self-control problems. Subjects also appear to have biased beliefs about their future cost of gym attendance. Our design allows us to estimate the monetary value of habit-formation equivalent to a forty cents per visit subsidy, as well as the welfare cost of naivete.In chapter two we address whether individuals accurately predict habit-formation, a question of both theoretical and practical interest. Gym-attendance is one domain in which this question is of particular interest to public policy makers. We test for mispredic-tion of habit-formation in gym attendance with a field experiment and find that subjects do form a habit, and do not predict it fully. We develop a simple model that incorporates habit-formation and projection bias in the framework of quasi-hyperbolic discounting and calibrate the parameters of the model.In chapter three, borrowing from Cognitive Heierarchy Theory, I introduce bounded rationality into the beta{delta model of present-biased preferences. I define a level-two agent, or k-2 sophisticate, as one who is aware that her future selves will have present-bias, but believes that they will be naive. The k-2 sophisticate does one round of strategic thinking about her future behavior instead of the unlimited number of rounds of the full so-phisticate. In the Doing it Once model of procrastination of O'Donoghue and Rabin (1999) the k-2 sophisticate typically procrastinates and preproperates less than the full sophisticate, and is protected from severe harm from both extreme preproperation and extreme procrastination, though she may suffer from excessive costly preemption due to pessimism about future preemption when costs are immediate