Frequent Subclinical Macular Changes in Combined Braf/Mek Inhibition With High-Dose Hydroxychloroquine as Treatment for Advanced Metastatic Braf Mutant Melanoma

Nti, Akosua; Serrano, Leona; Sandhu, Harpal S.; Uyhazi, Katherine E.; Edelstein, Ilaina D.; Zhou, Elaine; Bowman, Scott; Song, Delu; Gangadhar, Tara C.; Schuchter, Lynn M.; Mitnick, Sheryl; Huang, Alexander C.; Nichols, Charles W.; Amaravadi, Ravi K.; Kim, Benjamin J.; Alemán, Tomás S.

doi:10.1097/iae.0000000000002027

Cited by 29 publications

(29 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There were, however, examples of subretinal images that may correspond to accumulation of subretinal material, including inflammatory cells, migrated RPE cells and/or shed unphagocytized outer segments. The most consistent and dramatic change on imaging was the presence of round areas of hypo-AF (on SW- and NIR-FAF imaging) within the blebs that corresponded with loss of the IZ signal suggesting POS abnormalities or loss and demelanization of the RPE 45 . Readministration of the vector in the overlapping blebs led to overlapping additional depigmentation but did not lead to worsening of the existing changes.…”

Section: Discussionmentioning

confidence: 93%

Safety of Same-Eye Subretinal Sequential Readministration of AAV2-hRPE65v2 in Non-human Primates

Weed

Ammar

Zhou

et al. 2019

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

We have demonstrated safe and effective subretinal readministration of recombinant adeno-associated virus serotype (rAAV) to the contralateral eye in large animals and humans even in the setting of preexisting neutralizing antibodies (NAbs). Readministration of AAV to the same retina may be desirable in order to treat additional areas of the retina not targeted initially or to boost transgene expression levels at a later time point. To better understand the immune and structural consequences of subretinal rAAV readministration to the same eye, we administered bilateral subretinal injections of rAAV2-hRPE65v2 to three unaffected non-human primates (NHPs) and repeated the injections in those same eyes 2 months later. Ophthalmic exams and retinal imaging were performed after the first and second injections. Peripheral blood monocytes, serum, and intraocular fluids were collected at baseline and post-injection time points to characterize the cellular and humoral immune responses. Histopathologic and immunohistochemical studies were carried out on the treated retinas. Ipsilateral readministration of AAV2-hRPE65v2 in NHPs did not threaten the ocular or systemic health through the time span of the study. The repeat injections were immunologically and structurally well tolerated, even in the setting of preexisting serum NAbs. Localized structural abnormalities confined to the outer retina and retinal pigmented epithelium (RPE) after readministration of the treatment do not differ from those observed after single or contralateral administration of an AAV carrying a non-therapeutic transgene in NHPs and were not observed in a patient treated with the nearly identical, FDA-approved, AAV2-hRPE65v2 vector (voretigene neparvovec-rzyl), suggesting NHP-specific abnormalities.

show abstract

Section: Discussionmentioning

confidence: 93%

Safety of Same-Eye Subretinal Sequential Readministration of AAV2-hRPE65v2 in Non-human Primates

Weed

Ammar

Zhou

et al. 2019

Molecular Therapy - Methods & Clinical Development

Self Cite

View full text Add to dashboard Cite

show abstract

“…In cancer studies, the prescribed doses of hydroxy chloroquine can reach up to 1,200 mg daily. Despite such high doses, no relevant toxic adverse effects (beside cytopenia) were reported in these studies, even when hydroxychloroquine was combined with other oculo toxic agents [144][145][146][147][148] . However, the treatment periods for oncological conditions are generally much shorter than for rheumatic diseases, and therefore the cumulative dose is usually lower in patients with cancer than in patients with rheumatic diseases.…”

Section: Dosing Considerationsmentioning

confidence: 99%

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

2020

View full text Add to dashboard Cite

“…A separate imaging analysis software (http://imagej.nih.gov/ij/links.html, available in the public domain) was used to generate longitudinal reflectivity profiles from exported images and help supervise and correct automatic segmentation errors. [18][19][20] ''Retinal thickness'' was defined as the distance between the signal peak at the vitreoretinal interface (the internal limiting membrane [ILM]) and the posterior boundary of the major signal peak that corresponds to the basal retinal pigment epithelium/Bruch's membrane complex (RPE/BrM). In normal subjects, the RPE/BrM is the last reflectivity within the 4-6 signals that are identifiable in the outer retina.…”

Section: Retinal Imagingmentioning

confidence: 99%

“…In normal subjects, the RPE/BrM is the last reflectivity within the 4-6 signals that are identifiable in the outer retina. 20 In patients, the presumed RPE signal was sometimes the only signal in the outer retina and often merged with signals from the anterior choroid. The RPE/BrM peak intensity was then specified manually by considering the properties of the backscattering signal originating from layers vitread and sclerad to it.…”

Section: Retinal Imagingmentioning

confidence: 99%

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Alemán

Uyhazi

Serrano

et al. 2018

Invest. Ophthalmol. Vis. Sci.

Self Cite

View full text Add to dashboard Cite

PURPOSE. To describe the retinal phenotype of pediatric patients with mutations in the retinol dehydrogenase 12 (RDH12) gene. METHODS. Twenty-one patients from 14 families (ages 2-17 years) with RDH12-associated inherited retinal degeneration (RDH12-IRD) underwent a complete ophthalmic exam and imaging with spectral domain optical coherence tomography (SD-OCT) and near infrared and short-wavelength fundus autofluorescence. Visual field extent was measured with Goldmann kinetic perimetry, visual thresholds with dark-adapted static perimetry or with dark-adapted chromatic full-field stimulus testing (FST) and transient pupillometry. RESULTS. Visual acuity ranged from 20/40 to light perception. There was parafoveal depigmentation or atrophic maculopathies accompanied by midperipheral intraretinal pigment migration. SD-OCT revealed foveal thinning in all patients and detectable but thinned outer nuclear layer (ONL) at greater eccentricities from the fovea. Photoreceptor outer segment (POS) signals were only detectable in small pockets within the central retina. Measurable kinetic visual fields were limited to small (<5-108) central islands of vision. Electroretinograms were reported as undetectable or severely reduced in amplitude. FST sensitivities to a 467 nm stimulus were rod-mediated and reduced on average by~2.5 log units. A thinned central ONL colocalized with severely reduced to nondetectable conemediated sensitivities. Pupillometry confirmed the psychophysically measured abnormalities. CONCLUSIONS. RDH12-IRD causes an early-onset, retina-wide disease with particularly severe central retinal abnormalities associated with relatively less severe rod photoreceptor dysfunction, a pattern consistent with an early-onset cone-rod dystrophy. Severely abnormal POS but detectable ONL in the pericentral and peripapillary retina suggest these regions may become targets for gene therapy.

show abstract

Frequent Subclinical Macular Changes in Combined Braf/Mek Inhibition With High-Dose Hydroxychloroquine as Treatment for Advanced Metastatic Braf Mutant Melanoma

Cited by 29 publications

References 81 publications

Safety of Same-Eye Subretinal Sequential Readministration of AAV2-hRPE65v2 in Non-human Primates

Safety of Same-Eye Subretinal Sequential Readministration of AAV2-hRPE65v2 in Non-human Primates

Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology

RDH12Mutations Cause a Severe Retinal Degeneration With Relatively Spared Rod Function

Contact Info

Product

Resources

About