Update on Gene Therapy Clinical Trials for Choroideremia and Potential Experimental Therapies

Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (-6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (-1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had -17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (-14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies

Altered Antioxidant-Oxidant Status in the Aqueous Humor and Peripheral Blood of Patients with Retinitis Pigmentosa

Retinitis Pigmentosa is a common form of hereditary retinal degeneration constituting the largest Mendelian genetic cause of blindness in the developed world. It has been widely suggested that oxidative stress possibly contributes to its pathogenesis. We measured the levels of total antioxidant capacity, free nitrotyrosine, thiobarbituric acid reactive substances (TBARS) formation, extracellular superoxide dismutase (SOD3) activity, protein, metabolites of the nitric oxide/cyclic GMP pathway, heme oxygenase-I and inducible nitric oxide synthase expression in aqueous humor or/and peripheral blood from fifty-six patients with retinitis pigmentosa and sixty subjects without systemic or ocular oxidative stress-related disease. Multivariate analysis of covariance revealed that retinitis pigmentosa alters ocular antioxidant defence machinery and the redox status in blood. Patients with retinitis pigmentosa present low total antioxidant capacity including reduced SOD3 activity and protein concentration in aqueous humor. Patients also show reduced SOD3 activity, increased TBARS formation and upregulation of the nitric oxide/cyclic GMP pathway in peripheral blood. Together these findings confirmed the hypothesis that patients with retinitis pigmentosa present reduced ocular antioxidant status. Moreover, these patients show changes in some oxidative-nitrosative markers in the peripheral blood. Further studies are needed to clarify the relationship between these peripheral markers and retinitis pigmentosa

Regeneration of trabecular meshwork in primary open angle glaucoma by stem cell therapy: a new treatment approach

Enzo Maria Vingolo, Ayoub Chabib, Federico Anselmucci Department of Sense Organs, U.O.C. Ophthalmology, Sapienza University of Rome, Latina, Italy Abstract: Primary open angle glaucoma (POAG) is a worldwide disease with IOP being an important risk factor for the disease. Pharmacological and surgical treatments have been mainly targeted on lowering IOP by decreasing aqueous humor production or increasing aqueous humor outflow. Stem cell therapies may open new frontiers in regenerative ophthalmology branch. In POAG there is a strong association with pathologic degeneration of the trabecular meshwork (TM) and regenerative cell-therapy approaches have been focused mainly on modulation of the degeneration. Many different adult stem cell types have been discovered in different parts of the eye such as the corneal endothelium (CE) and anterior non-filtering portion of the TM called Schwalbe’s ring region. These stem cells may supply new cells for the TM and may regenerate the TM structure thus reducing IOP and restore the homeostatic function of the eye. In this paper, we report the studies’ latest findings and present our perspective on approaches that seem promising in the management of POAG. Keywords: glaucoma, trabecular meshwork, stem cell therapy, POAG, iPSC &nbsp

Corneal stromal demarcation line after collagen cross-linking in corneal ectatic diseases: a review of the literature

Leopoldo Spadea, Emanuele Tonti, Enzo Maria Vingolo Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy Abstract: Collagen cross-linking (CXL) is a relatively new conservative approach for progressive corneal ectasia, which is able to strengthen corneal tissue reforming new covalent bonds. Subjective and objective results following this method seem to be promising. In recent years, newer CXL protocols have been developed to perform more effective and less invasive procedures. The increasing diffusion of CXL in the corneal ectatic disease has increased the need to have actual indices regarding the efficacy of the treatment. Evaluation of demarcation line (DL), a transition zone between the cross-linked anterior corneal stroma and the untreated posterior corneal stroma, is considered a measurement of the depth of CXL treatment into the stroma. Some evidence in the literature emphasize that DL could be a measure of effectiveness of the CXL. On the contrary, some authors believe that the “the deeper, the better” principle is rather a simplistic approach for interpreting the clinical importance of the corneal stromal DL. Keywords: corneal cross-linking, demarcation line, keratoconus, ultraviolet

MP-1 Biofeedback: Luminous Pattern Stimulus Versus Acoustic Biofeedback in Age Related Macular degeneration (AMD)

In this study we evaluated the efficacy of visual rehabilitation by means of two different types of biofeedback techniques in patients with age related macular degeneration (AMD). Thirty patients, bilaterally affected by AMD, were randomly divided in two groups: one group was treated with an acoustic biofeedback (AB group), the other was treated with luminous biofeedback of a black and white checkerboard flickering during the examination (LB group). All patients underwent a complete ophthalmological examination. Rehabilitation consisted of 12 training sessions of 10 min for each eye performed once a week for both groups. Both groups showed better visual performance after rehabilitation and luminous flickering biofeedback stimulus showed a statistically significant improvement in training the patients to modify their preferred retinal locus in comparison to acoustic biofeedback. This suggests that it might be possible in the damaged retina to override dead photoreceptor and outer retinal layers and involve residual surviving cells, as well as amplify and integrate retinal and brain cortex plasticity by using other spared channels towards associative pathways

The Mozart effect in biofeedback visual rehabilitation: a case report

Serena Salvatore, Aloisa Librando, Mariacristina Esposito, Enzo M VingoloDepartment of Ophthalmology, University La Sapienza, Polo Pontino, Alfredo Fiorini Hospital, Terracina, ItalyPurpose: To evaluate the usefulness of acoustic biofeedback by means of Mozart’s Sonata for Two Pianos in D Major K. 448 to maintain and/or restore visual performance in a patient with macular pucker and glaucoma.Methods: A 74-year-old patient with open angle glaucoma in both eyes and macular pucker in the right eye (RE) underwent visual rehabilitation with acoustic biofeedback by means of the MAIA™ Vision Training Module (Centervue, Padova, Italy) 10 minutes each eye once a week for 5 weeks. The patient was asked to move his eyes according to a sound which changed into Mozart’s Sonata for Two Pianos when the patient locked the fixation target.Results: Best-corrected visual acuity improved in his right eye (RE) and was stable in the left eye (LE). Fixation stability improved in both eyes, and retinal sensitivity decreased in the RE and improved in the LE. The characteristic of the macular pucker did not change during the training as demonstrated with optical coherence tomography. The patient was very satisfied with the training, as demonstrated by a 25-item questionnaire (National Eye Institute – Visual Functioning Questionnaire, NEI-VFQ-25). The patient’s reading speed and the character size which he was able to read improved in his RE.Conclusion: Music could enhance synaptic plasticity and affect neural learning and fixation training by means of MAIA vision training. Therefore it can improve visual performance in patients with macular pucker, postpone the surgical time, and assure a better quality of life for the patient.Keywords: glaucoma, macular cellophane, music, vision trainin

Vitreal alterations in retinitis pigmentosa: Biomicroscopic appearance and statistical evaluation

The authors present a biomicroscopic evaluation of vitreal alterations in a large group of patients affected by primary retinitis pigmentosa (RP). 286 RP patients (571 eyes), 153 (305 eyes) males and 133 (266 eyes) females, have been studied; the mean age of this whole group was 37.26 ± 14.93 years (age range: 5-77). Vitreal static and dynamic biomicroscopy was performed on fully dilated pupils by means of a Haag-Streit 900 slit-lamp and high-power positive precorneal lenses (+90 and +78 dpt Volk lenses). Most patients showed floating cottonball-like condensations (26.824%) often associated with fibrillary degeneration (15.88%), while non-pigmentary vitreal particulation was detected in 26.609% of cases and the pigmentary type in 12.017%, respectively. Posterior vitreal detachment was detected alone in only 0.43% of cases while 18.24% of examined eyes showed no vitreal alterations. A high statistical correlation between vitreal aspects and pigmentary grading of the fundus oculi (p = 0.0001), as well as duration of the disease (p = 0.0074), was found; at the same time, no statistical correlation with refractive error was demonstrated (p = 0.47)

Low vision rehabilitation: current perspectives

Enzo Maria Vingolo, Vittoria De Rosa, Daniela Domanico, Federico Anselmucci  Department of Ophthalmology, University La Sapienza of Rome, Terracina, Italy Abstract: Quality of life in low vision patients is deeply conditioned by their visual ability, and increased rates of depression, domestic injury, and need for caregiver assistance can be expected as a result of low performance. Much effort have been made recently in order to develop new tools and aids for rehabilitation of low vision, and this research has led to better knowledge of visual function and increased the likelihood of new therapies in the future. Modern low vision rehabilitation is the result of recent advances in science and technology, and will soon have an important role in people with vision impairment, numbers of whom are likely to increase, give the increasing age of the population. This review outlines scientific developments in low vision rehabilitation based on a search of the literature, covers the role of digital technology and advances in neurofunctional rehabilitation, and the possibility of restoring vision by use of retinal prostheses and cellular therapy. Keywords: AMD, retinal dystrophy, biofeedback training, retinal prosthesis, stem cell

Regenerative Therapy by Suprachoroidal Cell Autograft in Dry Age-related Macular Degeneration: Preliminary In Vivo Report.

This study is aimed at examining whether a suprachoroidal graft of autologous cells can improve best corrected visual acuity (BCVA) and responses to microperimetry (MY) in eyes affected by dry Age-related Macular Degeneration (AMD) over time through the production and secretion of growth factors (GFs) on surrounding tissue. Patients were randomly assigned to each study group. All patients were diagnosed with dry AMD and with BCVA equal to or greater than 1 logarithm of the minimum angle of resolution (logMAR). A suprachoroidal autologous graft by Limoli Retinal Restoration Technique (LRRT) was carried out on group A, which included 11 eyes from 11 patients. The technique was performed by implanting adipocytes, adipose-derived stem cells obtained from the stromal vascular fraction, and platelets from platelet-rich plasma in the suprachoroidal space. Conversely, group B, including 14 eyes of 14 patients, was used as a control group. For each patient, diagnosis was verified by confocal scanning laser ophthalmoscope and spectral domain-optical coherence tomography (SD-OCT). In group A, BCVA improved by 0.581 to 0.504 at 90 days and to 0.376 logMAR at 180 days (+32.20%) postoperatively. Furthermore, MY test increased by 11.44 dB to 12.59 dB at 180 days. The different cell types grafted behind the choroid were able to ensure constant GF secretion in the choroidal flow. Consequently, the results indicate that visual acuity (VA) in the grafted group can increase more than in the control group after six months