Retina Update: New research challenges previous findings on genetic risk factor for AMD

Recently published findings of the role of a key genetic protein in the pathogenesis of age-related macular degeneration challenges existing thinking about how the protein contributes to disease progression. 

Researchers at the University of Utah reported that mRNA encoding the serine protease HTRA1 in people with a genetic predisposition to AMD is the strongest genetic risk factor for disease progression.¹ They’ve concluded that enhancing expression of the underlying HtrA1 protein—it stands for high-temperature requirement A1—would be a desirable target to treat AMD.

The researchers noted their observations contradict previously published reports that showed either no difference or elevated expression of HtrA1 in retinal tissue from donors with 10q26 risk.^2,3 Based on that research, Genentech applied for a patent on anti-HtrA1 antibodies and is conducting Phase II trials of the candidate FHTR2163, an intravitreal treatment that targets this novel pathway in geographic atrophy secondary to dry AMD. 

“While the specific role and impact of HtrA1 in geographic atrophy has not yet been fully established in a randomized clinical trial, multiple preclinical studies have shown that over-expression of HTRA1 in the retina is associated with atrophy of the retinal pigment epithelium and photoreceptors,” Genentech says in a statement. 

“Thus, it remains reasonable to hypothesize that geographic atrophy progression may be associated with elevated HtrA1 levels in the retina,” the company says. It cites a Phase I trial that showed anti-HtrA1 is safe in humans, and notes that the ongoing Phase II GAllego and GAllegOLE trials “will provide further data on safety and efficacy of anti-HtrA1, and should further our understanding of HtrA1’s role in geographic atrophy.”

Role of HtrA1 protein

Brandi Williams, PhD

Studying what they described as a “extensive repository of donated human ocular tissues,” the Utah researchers reported that the HtrA1 protein increases with age in the retinal pigment epithelium-Bruch’s membrane interface, helping to maintain normal function in the region, in donor eyes with the 10q26 (Chr10) locus, which has been identified as the strongest genetic risk factor for AMD. The 10q26 locus contains the ARMS2 and the HTRA1 genes.

The repository consists of more than 8,000 pairs of donated human eyes at the University of Utah’s Sharon Eccles Steele Center for Translational Medicine (SCTM). “One of the huge strengths of the study was that we were using human donor tissue, not a cell culture model nor differentiated RPE cells,” lead author Brandi Williams, PhD, tells Retina Specialist. “Hundreds of samples were used. We found a huge range of expression, but the effect is small, so having as many as samples as we had really solidifies the findings.” 

She notes that previous studies used few samples and didn’t observe any differences in retinal tissues. “We really felt we observed a tissue- specific effect,” Dr. Williams says. The researchers developed a specific assay to confirm their findings. 

Focus of future research

The Utah study examined donor eyes that didn’t have AMD. Chr10 is a risk factor for both forms of AMD, Dr. Williams says, and the under-expression of HTRA1 can drive both forms of the disease. Dr. Williams adds that HtrA1 may have a role in maintaining healthy vasculature and that its under-expression may contribute to other vascular diseases.

The Utah research team is focusing on further investigating the functional effects HtrA1 has in the RPE-Bruch’s membrane interface and is pursuing proof-of-concept studies for gene therapy approaches for enhancing HRTA1 expression. RS

Dr. Williams and other co-authors are inventors on patents and patent applications owned by the University of Utah.

REFERENCES

<sup>1. Williams BL, Seager NA, Gardiner JD, et al. Chromosome 10q26-driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium. Proc Natl Acad Sci U S A. 2021;118:e2103617118. doi:10.1073/pnas.2103617118
2. Yang Z, Camp NJ, Sun H, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992-993.
3. Chan CC, Shen D, Zhou M, et al. Human HtrA1 in the archived eyes with age-related macular degeneration. Trans Am Ophthalmol Soc. 2007;105:92-97;discussion 97-98.</sup>

Retina Specialist welcomes five to editorial board Retina Specialist magazine has expanded its editorial board with the addition of five new board members. They are: Caroline Baumal, MD • Caroline Baumal, MD, professor of ophthalmology at New England Eye Center, Tufts Medical Center in Boston. She specializes in medical and surgical disorders of the retina and vitreous, with research interests focusing on novel retinal imaging and drug development. Justis P. Ehlers, MD • Justis P. Ehlers, MD, the Norman C. and Donna L. Harbert Endowed Chair of Ophthalmic Research and director of the Tony and Leona Campane Center for Excellence in Image-Guided Surgery and Advanced Imaging Research at the Cole Eye Institute of the Cleveland Clinic. Dr. Ehlers’ clinical expertise is in the treatment and management of vitreoretinal diseases and advanced ophthalmic imaging.   Avni Finn, MD, MBA • Avni Finn, MD, MBA, a vitreoretinal surgeon with Northern California Retina Vitreous Associates in the San Francisco Bay area. Among Dr. Finn’s research interests are new techniques for macular hole surgery, intraoperative optical coherence tomography imaging, and biomarkers of atrophy and scar in macular degeneration.  Mrinali Gupta, MD • Mrinali Gupta, MD, a vitreoretinal surgeon at Retina Associates of Orange County, with offices in Newport Beach, Laguna Hills and Santa Ana, Calif. Previously, Dr. Gupta served for five years as vitreoretinal surgeon and assistant professor of ophthalmology at Weill Cornell Medical College in New York. Dr. Gupta currently serves as vice president of education on the executive committee of the Vit-Buckle Society.   Amir H. Kashani, MD, PhD • Amir H. Kashani, MD, PhD, associate professor of ophthalmology at Wilmer Eye Institute, Johns Hopkins University in Baltimore. His research interests include retinal imaging, and he’s the principal investigator of a novel stem cell treatment for geographic atrophy. He was formerly an associate professor and clinical scholar at the University of Southern California.

Breaking down wrong-site injections

Wrong-site intravitreal injections are extremely rare events. The Ophthalmic Mutual Insurance Company reported that it analyzed 51 malpractice claims for intravitreal injections—not specifying the nature of the claims—for the period from 1987 to 2016, while in 2017 alone 7 million such injections were performed.¹ In a recent study published in JAMA Ophthalmology, researchers from Kaiser Permanente North California in Oakland reported on four such cases out of more than 147,000 intravitreal injections over two years in their health system.² 

Nonetheless, they analyzed the errors and identified key lapses in protocol in all the cases. Those lapses included making mistakes in reviewing the electronic medical record, lack of surgeon and staff focus, and inconsistent use of surgical checklists and  timeouts. 

Robin A. Vora, MD

Lead author Robin A. Vora, MD, of KPNC, explains to Retina Specialist the relevance of the findings despite the rare incidence of wrong-site IVI. 

“As our population continues to age, the practice of a retina specialist has become increasingly busy,” he says. “We serve the growing number of patients who require care for macular degeneration, diabetic retinopathy and other chronic conditions. This comes with an increase in the number of therapeutic choices, along with insurance cost and supply constraints, and the fact that a single patient may require care in one or both eyes, often at different intervals and with different agents.  

“Taken together,” Dr. Vora adds, “it becomes clear that precautions must ensure that a physician completes the procedure safely and effectively. This is no different than what all surgeons are required to do in the operating theatre: to ensure the correct procedure to the correct eye. Checklists and ‘time-outs’ are an essential part of such precautions.”

None of the study patients suffered long-term consequences from the erroneous injections. “However,” says Dr. Vora, “given that the complication rate for this procedure is non-zero, no future harm is not guaranteed. It’s our sincere hope that by sharing our experience, we can inform our colleagues worldwide to adopt safety protocols to make the performance of this common procedure as safe as possible for patients.” RS

Dr. Vora and co-authors have no relationships to disclose.