Inflammasomes in Cell Death in FTMH, ERM, and RRD

Retinal Detachment Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03332758
• Other study ID #: 17-660E
• Status: Completed
• Start date: September 8, 2017
• Est. completion date: May 1, 2018

Study information

• Verified date: August 2018
• Source: Wills Eye
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: May 1, 2018
• Est. primary completion date: April 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Epiretinal Membrane
• Full Thickness Macular Hole
• Retinal Detachment
• Retinal Perforations

Intervention

Procedure:
• Pars plana vitrectomy
Standard of care treatment for retinal detachment, macular hole, or epiretinal membrane.
• External drainage
Standard of care treatment for retinal detachment.

Locations

Country	Name	City	State
United States	MidAtlantic Retina-Wills Eye Hospital	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Allen C. Ho, MD	Mid Atlantic Retina

Country where clinical trial is conducted

United States, 

References & Publications (2)

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:e1731. doi: 10.1038/cddis.2015.73. — View Citation

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Difference in inflammasome levels among samples	Difference in inflammasome pathway activation between retinal detachment, macular hole, and epiretinal membrane samples	Day of surgery