Inflammasomes in Cell Death in FTMH, ERM, and RRD

Inflammasomes in Cell Death in Macular Hole, Epiretinal Membrane, and Rhegmatogenous Retinal Detachment

Prospective study evaluating the role of inflammasomes in cell death in retinal detachment, full thickness macular hole, and epiretinal membrane. The investigators are collecting vitreous and subretinal fluid samples from patients with these conditions and evaluating activity of the inflammasome pathway with established assays.

Study Overview

• Status: Completed
• Conditions: Retinal Detachment; Epiretinal Membrane; Full Thickness Macular Hole
• Intervention / Treatment: Procedure: Pars plana vitrectomy; Procedure: External drainage

Detailed Description

Photoreceptor cell death is the main cause of vision loss in many retinal disorders, including retinal detachment (RD). While apoptosis is the most studied form of cell death, the investigators believe patients with RDs may have photoreceptor cell death from a distinct pathway of programmed cell death called pyroptosis which also involves an inflammatory response. Pyroptosis is distinct from apoptosis in that it requires the activation of a protein oligomer complex called an inflammasome. The inflammasome is a pro-inflammatory complex composed of apoptosis-associated speck-like protein containing a CARD (ASC), nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor (NLR) family or pyrin and HIN domain (PYHIN) family, and caspase-11. Activation of the inflammasome complex leads to activation of capspase 1 proteolytic activity to cleave and synthesize IL-1β and IL-18. As such the investigators believe inflammasomes and its activated products may play a strong role in the inflammatory and cell death pathway for photoreceptor cells in human retina. Studies using animal models of RD have already confirmed the presence of IL-1β activation2, however, the presence of IL-18 needs to be confirmed in human detached retinas. In a study performed on the detached retinas in mice, researchers were able to show activation of inflammasomes leading to photoreceptor cell death. While researchers are unable to determine the cellular source of the inflammasomes they were able to show that activation inflammasomes closely follows animal models. Currently there is no method to rescue photoreceptors cells from the mediated cell death pathway despite surgical intervention. Thus, current visual prognosis and prevention of further photoreceptor loss due to a RD is likely dependent on the time of surgical intervention before further detachment and further cell death can occur. As such, the purpose of this current study is to confirm the presence of inflammasome activation as well as the synthesis of its products, IL-1β and IL-18, in patients with rhegmatogenous retinal detachments. Both inflammasomes and its products IL-1β and IL-18 may be involved in cell pyroptosis, a programmed cell death distinct from apoptosis. Due to a lack of treatment for the rescue of photoreceptor cells from cell death after a retinal detachment, this study can provide novel strategies to inhibit cell death.

• Study Type: Observational
• Enrollment (Actual): 41

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • MidAtlantic Retina-Wills Eye Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Adults with retinal detachment, macular hole, or epiretinal membrane.

Description

Inclusion Criteria:

1. Patient of the Wills Eye Hospital Retina service and Mid-Atlantic Retina offices.
2. Volunteer patients age 18 years and older.
3. Healthy enough to participate in the study.
4. Willing and able to consent to participation in the study.
5. Diagnosis of rhegmatogenous retinal detachment treated with external drainage of subretainl fluid, rhegmatogenous retinal detachment treated with pars plana vitrectomy, or full thickness macular hole treated with pars plana vitrectomy

Exclusion Criteria:

1. Presence of tractional retinal detachment
2. History of trauma
3. Presence of proliferative vitreoretinopathy
4. History of prior retinal detachment repair or any prior retina surgery or laser treatment e. Any preexisting retinal disease (including diabetic retinopathy, age related macular degeneration, retinal vein or artery occlusion, other retinal vascular disease, inherited retinal degeneration, uveitis)

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
RD treated with vitrectomy; Vitreous fluid from retinal detachment treated with pars plana vitrectomy	Procedure: Pars plana vitrectomy; Standard of care treatment for retinal detachment, macular hole, or epiretinal membrane.
RD treated with external drainage; Subretinal fluid from retinal detachment treated with external drainage.	Procedure: External drainage; Standard of care treatment for retinal detachment.
Macular holes treated with vitrectomy; Vitreous fluid from patients treated for macular hole	Procedure: Pars plana vitrectomy; Standard of care treatment for retinal detachment, macular hole, or epiretinal membrane.
ERM treated with vitrectomy; Vitreous fluid from patients treated for epiretinal membrane	Procedure: Pars plana vitrectomy; Standard of care treatment for retinal detachment, macular hole, or epiretinal membrane.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence of inflammasomes and their active products	Presence of inflammasomes and their active products in patients with retinal detachment treated with vitrectomy or external drainage, macular holes treated with vitrectomy, and epiretinal membranes treated with vitrectomy	Day of surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in inflammasome levels among samples	Difference in inflammasome pathway activation between retinal detachment, macular hole, and epiretinal membrane samples	Day of surgery

Collaborators and Investigators

• Sponsor: Allen C. Ho, MD
• Collaborators: Mid Atlantic Retina
• Investigators: Principal Investigator: Allen C Ho, MD, MidAtlantic Retina

Publications and helpful links

General Publications

• Murakami Y, Notomi S, Hisatomi T, Nakazawa T, Ishibashi T, Miller JW, Vavvas DG. Photoreceptor cell death and rescue in retinal detachment and degenerations. Prog Retin Eye Res. 2013 Nov;37:114-40. doi: 10.1016/j.preteyeres.2013.08.001. Epub 2013 Aug 28.
• Kataoka K, Matsumoto H, Kaneko H, Notomi S, Takeuchi K, Sweigard JH, Atik A, Murakami Y, Connor KM, Terasaki H, Miller JW, Vavvas DG. Macrophage- and RIP3-dependent inflammasome activation exacerbates retinal detachment-induced photoreceptor cell death. Cell Death Dis. 2015 Apr 23;6(4):e1731. doi: 10.1038/cddis.2015.73.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 8, 2017
• Primary Completion (ACTUAL): April 10, 2018
• Study Completion (ACTUAL): May 1, 2018

Study Registration Dates

• First Submitted: October 13, 2017
• First Submitted That Met QC Criteria: November 1, 2017
• First Posted (ACTUAL): November 6, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 17, 2018
• Last Update Submitted That Met QC Criteria: August 15, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: macular hole; inflammasome; retinal detachment
• Additional Relevant MeSH Terms: Eye Diseases; Retinal Diseases; Retinal Perforations; Retinal Detachment; Epiretinal Membrane
• Other Study ID Numbers: 17-660E

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: manuscript under development

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No