Gene Therapy Strategies for Diabetic Eye Diseases

Nachi Pendse, PhD - November 23, 2021

In this blog post, Patricia D’Amore, PhD, MBA; Sui Wang, PhD; and Nachi Pendse, PhD; shared some of their insights on how cell and gene therapy can help patient populations with diabetic eye disorders.

In recognition of Diabetic Eye Disease Awareness month, Nachi Pendse, PhD, teamed up with Patricia D’ Amore, PhD, MBA, (vice chair, basic and translational research, department of ophthalmology, Harvard Medical School) and Sui Wang, PhD (assistant professor, department of ophthalmology, Stanford University).

What is Diabetic Eye Disease?

Diabetic eye disorders are eye diseases that affect people with diabetes (type 1 and type 2). Diabetic eye disease can cause severe vision loss or even blindness. Diabetic eye diseases include:

  • Diabetic retinopathy—damage to the blood vessels in the retina

  • Cataract—clouding of the lens of the eye

  • Glaucoma—increase in fluid pressure inside the eye that damages the optic nerve

Worldwide, from 2015-2019, 27% of people with diabetes developed diabetic retinopathy. This breaks down into 25.2% of that group having non-proliferative diabetic retinopathy (retinal changes that include microaneurysm, capillary drop-out, etc.) and 1.4% having proliferative diabetic retinopathy, while 4.6% of diabetic patients display diabetic macular edema. Most individuals with type 1 diabetes and 60% of people with type 2 diabetes have some form of diabetic retinopathy. Based on a recent study published in Ophthalmology, the number of adults with diabetic eye disorders was estimated to be around 100 million worldwide. In the U.S., the number of adults with diabetic eye diseases was estimated to double between 2010 and 2050, from 7.7 million to 14.6 million, per National Eye Institute Diabetic Retinopathy Data and Statistics.

What Are the Key Genes Affected or Involved?

There has been a good deal of research to identify genes that are involved in diabetic eye diseases. One study indicated a role for genetics in susceptibility and severity of diabetic retinopathy, showing the heritability of DR to be 27%. The development of these complications of diabetes are largely influenced by lifestyle variables such as control of the diabetes, blood pressure, cholesterol, and smoking. Many other genetic studies in diabetic eye disorders, especially diabetic retinopathy, have revealed  several genes and pathways to be key players, including ACE (angiotensin-I converting enzyme), AGTR1 (angiotensin II Type 1 receptor), AGT (angiotensinogen), PAI-1 (plasminogen activator inhibitor-1), PPARG (peroxisome proliferator-activated receptor gamma), NOS3 (nitric oxide synthase 3), VEGF (vascular endothelial growth factor​​), ALR2 (aldose reductase), RAGE (receptor for AGEs), glut1 (glucose transporter 1), and TGFB1 (transforming growth factor beta).

Key Risk Factors Include:

  • Family history of diabetes
  • Obesity
  • High blood pressure, high cholesterol and triglycerides
  • Gestational diabetes

What is the Current Gap in Our Knowledge for Developing Next Generation Therapies for Diabetic Eye Disorders?

Prevention or cure of the diabetes itself would obviously eliminate the diabetic eye disorders. For type 1 diabetes, this means beta cell replacement (or prevention of their loss). Rigorous glucose control has been shown to reduce diabetic complications, particularly in the eye and kidney. For type 2 diabetes, which is largely insulin resistance, a better understanding of metabolic syndrome would be essential. That said, weight loss can reverse or put the diabetes into remission. A recent study called DIRECT (Diabetes Remission Clinical Trial) conducted in the UK reported remission among people who lost significant weight—more 20 pounds— and maintained the weight loss over one to two years.

Beyond the correction of the disease itself, the key to preventing late-stage ocular pathology such as proliferative diabetic retinopathy is to lessen the earlier changes that include impairment of blood flow and loss of pericytes (capillary associated smooth muscle-like cells), which leads to the formation of microaneurysms, fluid leakage, capillary dropout, and eventually neovascularization. One cell replacement strategy has been shown to replace the lost pericytes; several pre-clinical studies in animal models have shown that delivery of mesenchymal stem cells or pericytes may associate with pericyte-free vessels and reduced disease progression. Diabetic macular edema and proliferative diabetic retinopathy are both being treated using intraocular anti-VEGF therapy, which serves to tighten micro vessels and reduce their permeability as well as block the growth of new blood vessels. Advances in this area include development of therapies with better durability (e.g. requiring fewer intravitreal injections). One approach has been to deliver anti-VEGF using viral vectors; these treatments are currently in clinical trials.

Despite significant success, current treatment options for DR, including anti-VEGF drugs and steroids, surgical removal of vitreous opacities and photocoagulation, have limitations. Intraocular injection of anti-VEGF drugs or steroids needs to be performed repeatedly. A significant portion of patients do not respond to the treatment. In addition, considering the well-known neuronal protective effect of VEGF, long-term treatment via anti-VEGF drugs may be harmful for retinal neurons. Photocoagulation and surgeries are largely palliative. Notably, all these treatments target the advanced stages of DR. They do not restore vision loss. One of the ways to protect vision under diabetic conditions is by blocking the initiation and early progression of DR before vision is compromised. However, the molecular mechanisms that underlie the initiation of DR are still not fully elucidated. 

Current Progress to Help Patients

A leader in beta cell replacement is Harvard University’s Doug Melton, PhD, as well as biotechs including Vertex Pharmaceuticals that are conducting clinical trials on encapsulated beta cells. Also rapidly progressing are artificial pancreas systems that provide closed-loop control. Nearly all the advances in anti-VEGF therapy are happening at biotech and pharmaceutical companies. These include adenoviral expression, slow release by nanoparticles, port delivery, and development of bi-specific antibodies that target other aspects of the pathologic pathway. Since there are a significant number of patients who do not respond to anti-VEGF there are also efforts to target other potential mediators of the elevated permeability and angiogenesis that characterize diabetic macular edema and proliferative diabetic retinopathy. To mention a few, Timothy Kern, PhD, Patrice Fort, PhD, and Thomas Gardner, MD, and many others have done essential work in uncovering the early responses of the retina to diabetes. Manipulation of these responses may protect the retina from diabetes-induced damage at early stages. 

Therapeutic Intervention Using Gene Editing and Gene Therapy

Gene therapy has great potential in helping patients with diabetic eye disorders, especially diabetic retinopathy. Since no genes with a major impact on the development of diabetic eye complications have been identified, it is not clear that there is a gene therapy approach (at least at this time). Current gene therapy strategies for treating diabetic retinopathy focus on inhibiting neovascularization and neurovascular degeneration in the retina. Several of these strategies have shown promising results in animal models. Regarding cell therapy, the most “upstream” solution for type I diabetes is to replace the beta pancreatic cells. At the specific level of the eye diseases, preclinical studies have been conducted suggesting that mesenchymal stem cells can be used to replace pericytes that are selectively lost during background retinopathy. With the advance of the AAV delivery system and better understanding of the pathology of diabetic retinopathy, gene therapy for this disease could become available in the near future.

Early Diagnosis Can Help Patients Prolong Their Vision

Diabetic eye disorders can impair vision, most often without any noticeable pain, discomfort, or changes in vision. Early diagnosis helps because glucose control has been shown to be the most effective way to decrease these side effects of diabetes, particularly for type 1. For type 2 diabetes weight loss can often reverse the diabetes and therefore prevent the development of complications. Even without weight loss, there are a number of medications that attenuate the insulin resistance that characterizes type 2 diabetes. Diabetic macular edema and proliferative diabetic retinopathy are currently treated using either laser photocoagulation or more recently (in the last decade) anti-VEGF therapy. Generally speaking, the earlier these therapies are started the more vision is retained.  

The National Institutes of Health recently published the Diabetes and Healthy Eyes Toolkit which includes resources to help educate people about diabetic eye disease. The potential for blindness caused by diabetes may be lessened by educating patients with diabetes as well as their family and friends about the importance of getting a dilated eye exam at least once a year. Thus, such educational programs can make a big difference guiding our community towards better health!

Dr. Pendse is senior project lead scientist at Novartis and a member of ASGCT's Communications Committee.