Waiting on a treatment: How the history of MacTel is leading us into the future

(Image credit: AdobeStock/Elena)

Macular telangiectasia type 2 (MacTel) is a rare, progressive disease of the macula, which typically affects patients older than 40 years and causes central visual field defects, parafoveal scotomas, and a significant reduction in visual acuity, particularly in near vision.¹ These changes can have a deleterious effect on patients’ ability to perform tasks essential to daily living, such as reading or driving, and can meaningfully reduce their health-related quality of life.² Our understanding of MacTel has transformed in recent decades, and potential therapies hold promise for patients who continue to lose their vision from this disease.

Pathophysiology of MacTel: An evolution in understanding

Initially, MacTel was considered a vascular disorder due to the prominent vascular changes that occur as the disease progresses, particularly in the telangiectatic vessels; it was believed that the outer retinal atrophy and retinal pigment epithelium (RPE) metaplasia observed in MacTel was caused by chronic exudation originating from this telangiectasia.¹ However, several factors cast doubt on this theory, including the following³:

• The presence of atrophy in the outer neurosensory retina, which is primarily supplied by the choroid
• A localized loss of macular pigment, which has not been observed in other retinal vascular diseases
• The fact that areas of macular pigment loss in MacTel are larger than the vascular alterations visible
  on angiography

We now understand MacTel to be a neurodegenerative disorder, wherein Müller cells, glial cells that surround and provide nourishment to retinal neurons, become dysfunctional, which causes progressive neuronal atrophy and disorganization of the outer retina over time. There is evidence for a genetic component that contributes to this dysfunction; the presence of systemic disorders, like diabetes and obesity, and ocular conditions, like soft confluent drusen and epiretinal membranes, may also play a role.¹ These findings have important implications for the development of potential therapies for patients with MacTel, especially the identification of Müller cell degeneration as a key pathophysiologic mechanism.

MacTel:A challenging diagnosis

Diagnosing MacTel can be challenging due to subtle features that overlap with many other conditions, like diabetic retinopathy, retinal vein occlusion, and other retinopathies.⁴ This, possibly combined with low awareness of the disease, leads to delay and inaccuracy in the diagnosis of MacTel.³ Although still considered a rare disease, there is also evidence that MacTel is underdiagnosed and may be more prevalent than once believed.⁵

In the past, diagnosis of MacTel was typically performed with fundus photography, to look for right-angled vessels, and fluorescein angiography (FA) to identify vascular leakage.¹ Currently, optical coherence tomography (OCT) angiography may be the best single method for diagnosing MacTel, due to its ability to more sensitively detect structural changes such as vessel density, differential involvement of retinal plexuses, and retinal neovascularization.⁶ However, multimodal imaging using OCT, OCT angiography, and FA together is preferable.

Management of MacTel: Hope on the horizon?

Unfortunately, there are no FDA-approved therapies for MacTel. If a patient came to us 10 years ago with a MacTel diagnosis, there was not much we could do for them beyond attempting vision rehabilitation. The use of oral carbonic anhydrase inhibitors was investigated for the treatment of MacTel, and although some anatomical features such as cystoid cavities and central macular thickness were found to improve, visual acuity was not improved.⁷ The subretinal neovascularization that may occur in later-stage MacTel can be treated with anti-VEGF therapies, but anti-VEGF agents have not demonstrated efficacy in nonproliferative MacTel and may potentially worsen photoreceptor degeneration.¹

Our current understanding of the pathophysiological basis of MacTel has led to the development of novel therapeutic approaches that may be able to break ground in this disease state. I am excited by the potential of NT-501; NT-501 is a surgically implanted encapsulated cell therapy that contains genetically modified RPE cells, which produce ciliary neurotrophic factor, a protein that provides neuroprotection to the photoreceptors. NT-501 was found to be generally well tolerated in a phase 1 trial (NCT01327911), and in phase 2 (NCT04729972) and 3 clinical trials (NCT03316300 and NCT03319849), NT-501 demonstrated a slowed progression of retinal degeneration, as measured by ellipsoid zone loss and loss of retinal sensitivity.^8,9 NT-501 is under review by the FDA, with a Prescription Drug User Fee Act date of March 18, 2025.¹⁰

Conclusions

The possibility of an approved therapy for MacTel brings hope for our patients but also underscores the need for greater awareness and training among eye care providers to be able to accurately identify this disease. I would encourage colleagues to familiarize themselves with the signs of MacTel so that we can be adequately poised to offer the best care to our patients.

I would also encourage retina specialists to familiarize themselves with ongoing clinical trials in MacTel and inform eligible patients so they can get the most cutting-edge care. Although MacTel can be devastating for those affected, the meaningful strides we have made toward understanding and potentially treating MacTel represent a triumph for our field. •

References

1. Kedarisetti KC, Narayanan R, Stewart MW, Reddy Gurram N, Khanani AM. Macular telangiectasia type 2: a comprehensive review. Clin Ophthalmol. 2022;16:3297-3309. doi:10.2147/OPTH.S373538

2. Clemons TE, Gillies MC, Chew EY, et al; Macular Telangiectasia Research Group. The National Eye Institute Visual Function Questionnaire in the Macular Telangiectasia (MacTel) Project. Invest Ophthalmol Vis Sci. 2008;49(10):4340-4346. doi:10.1167/iovs.08-1749

3. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Prog Retin Eye Res. 2013;34:49-77. doi:10.1016/j.preteyeres.2012.11.002

4. Jayasri P, Stephen AM. A complete clinical review of idiopathic macular telangiectasia. Oman J Ophthalmol. 2023;16(3):421-426. doi:10.4103/ojo.ojo_170_22

5. Klein R, Blodi BA, Meuer SM, Myers CE, Chew EY, Klein BE. The prevalence of macular telangiectasia type 2 in the Beaver Dam eye study. Am J Ophthalmol. 2010;150(1):55-62.e2. doi:10.1016/j.ajo.2010.02.013

6. Toto L, Di Antonio L, Mastropasqua R, et al. Multimodal imaging of macular telangiectasia type 2: focus on vascular changes using optical coherence tomography angiography. Invest Ophthalmol Vis Sci. 2016;57(9):OCT268-OCT276. doi:10.1167/iovs.15-18872

7. Chen JJ, Sohn EH, Folk JC, et al. Decreased macular thickness in nonproliferative macular telangiectasia type 2 with oral carbonic anhydrase inhibitors. Retina. 2014;34(7):1400-1406. doi:10.1097/IAE.0000000000000093

8. Chew EY, Clemons TE, Jaffe GJ, et al; Macular Telangiectasia Type 2-Phase 2 CNTF Research Group. Effect of ciliary neurotrophic factor on retinal neurodegeneration in patients with macular telangiectasia type 2: a randomized clinical trial. Ophthalmology. 2019;126(4):540-549. doi:10.1016/j.ophtha.2018.09.041

9. DeFino A. Macular telangiectasia cell therapy meets primary endpoints in phase 3 trials. Ocular Surgery News. January 18, 2024. Accessed November 13, 2024. https://www.healio.com/news/ophthalmology/20240118/macular-telangiectasia-cell-therapy-meets-primary-end point-in-phase-3-trial

10. FDA extends review period for MacTel therapy. Retinal Physician. November 12, 2024. Accessed December 20, 2024. https://www.retinalphysician.com/news/2024/fda-extends-review-period/

Rishi Singh, MD

e: SINGHR@ccf.org

Singh is vice president and chief medical officer of Cleveland Clinic Martin North and South Hospitals in Stuart, Florida. Singh reports having received personal fees from Alcon, Apellis Pharmaceuticals, Bausch + Lomb, Eyepoint Pharmaceuticals, Genentech, Iveric Bio, Regeneron, REGENXBIO, and ZEISS. Singh reports having received research grants from Johnson & Johnson Innovative Medicine.