Retinal ganglion cell (RGC) apoptosis and failure of optic nerve (ON) axon regeneration contribute to profound visual loss after traumatic optic neuropathy (TON), for which clinically effective treatments are lacking. Experimental manipulations of cellular signalling have identified phosphoinositide-3-kinase (PI3K) and its downstream mediators mTOR and GSK3\(\beta\) as important regulators of neuronal survival and axon regeneration in an animal model of TON, using targeted siRNA to knock-down key negative regulators of cellular signalling, and to investigate underlying mechanisms using retinal cultures. Intravitreal treatment with siRNA targeting RTP801, a stress-induced inhibitor of mTOR, promoted RGC survival and axon elongation after ON crush (ONC), and potentiated reactive gliosis. In vitro, siRTP801- induced neuroprotection was direct, but required GFAP\(^+\) activated retinal glia to stimulate neurite elongation. siRTP801 also potentiated levels of glial-derived Trk-dependent neurotrophic factors. Knock-down of the axon growth cone/apoptosis regulator GSK3\(\beta\) was also neuroprotective, promoted modest axon elongation after ONC, and increased neurite sprouting in vitro. GSK3\(\beta\) suppression counteracted neurite growth-inhibition induced by CNS myelin-derived Nogo. Combined treatment with siRTP801/siGSK3\(\beta\) augmented axon regeneration after ONC. These findings support a clinically translatable siRNA approach targeting PI3K/mTOR signalling as the basis for development of novel neuroprotective/axogenic therapies.

The core function of optometrists is the prescribing of spectacles in order to alleviate symptoms and improve visual function. Most commonly, the spectacles are used to correct refractive errors and, less frequently, they are also used to correct a decompensated heterophoria. Whilst identifying and diagnosing a marked refractive error or decompensated heterophoria is relatively straightforward, the management of marginal or borderline cases is much more difficult, for there is no clear cut-off point between normality and abnormality. The literature search in this thesis reveals a lack of evidence-based research on the criteria for determining when a refractive or prismatic correction is required. The aim of the present research was to investigate at what point optometrists currently decide to prescribe spectacles in borderline cases, and to see if current prescribing habits relate to the advice given in the literature. Further aims were to investigate whether the correction of borderline refractive errors and decompensated heterophoria improves reading performance, and to investigate any association between an improvement in reading performance and symptoms. A practitioner survey was given to practitioners attending CET events during 2001 and to the UK Optometry E-mail discussion list. A wide variety of prescribing criteria were reported from the 37 respondents, and the presence of symptoms greatly influenced the decision to prescribe. Practitioners reported that their likelihood of prescribing when symptoms are present exceeded 50% for: horizontal aligning prism of ≥ 1.5Δ, vertical aligning prism ≥ 1.0Δ, hypermetropia of ≥ +0.75, reading additions of ≥ +0.75DS and astigmatism of ≥ -0.75DC. For asymptomatic patients, practitioners’ likelihood of prescribing exceeded 50% for: reading additions of ≥+1.50DS and astigmatic corrections of ≥-1.50DC. In the absence of symptoms, optometrists would not regularly correct any degree of hypermetropia or aligning prism up to the limits of the survey. In a prospective clinical trial, 58 subjects with decompensated heterophoria and 208 subjects with borderline refractive errors had their reading performance assessed with the Wilkins Rate of Reading Test both with the refractive or prismatic lens in place and with a placebo control lens using a double-masked randomised design. Analysis of the data indicated that prescribing prism for decompensated exophoria of 2Δ, a reading addition of +1.00DS and correcting oblique cylindrical errors is likely to result in an improvement in reading performance. Correlations between symptoms and the change in reading performance with small refractive or prismatic corrections were very weak. It is concluded that the correction of borderline decompensated heterophoria and refractive errors can improve rate of reading. Guidelines are suggested for the correction of these anomalies that are based on the present data on visual performance, as well as the literature on the effect of these anomalies on symptoms.