Department of Ophthalmology
Schepens Eye Research Institute
Harvard Medical School, Boston, Massachusetts

BASIC RESEARCH PROJECT

A novel lipid nanoparticle for the treatment of retinal diseases

Research Interests

New treatment modalities are desperately needed to treat degenerative retinal conditions such as age-related macular degeneration. As our knowledge of the ways that these diseases happen increases, the number of candidate pathways that may be targeted to create novel treatments has increased. This may allow us to address many diseases with a common treatment. For example, many different retinal diseases have metabolic dysfunction and oxidative stress as causes. We now know genes that can activate and upregulate the body’s own coping mechanisms to these stresses. If we could selectively turn on one of those genes, that might be protective across many different types of retinal diseases. However, we need to have better ways to manipulate these therapeutic target genes. Adeno-associated viral vectors (AAVs) have been at the forefront of delivering therapeutic genes in the eye. This is because these viruses can be injected into the eye and lead to a very long duration of infection, and thus expression of their therapeutic gene. However, they have several limitations. We and others have noted that AAVs may cause unintended inflammation in the eye and toxicity, which may act as a limitation on the beneficial effects of the therapeutic genes they deliver. In addition, it may not always be desirable to have permanent overexpression of a gene in a tissue – as this concept is so new, it may be years before a harmful effect is recognized, and there is currently no way to silence an AAV infection once it has been performed. Lipid nanoparticles (LNPs) represent an alternative means to deliver mRNAs that modulate gene expression, without the downsides of AAVs. Lipid nanoparticles are tiny spheres, around 100-200 nanometers in size, with a nanometer being a billionth of a meter. They are so small they can pass through or be incorporated into cells. They can be designed to carry payloads composed of special molecules that can turn down some of the major destructive stress pathways into the eye, protecting key cells from damage during injury. Here, we propose to study and further develop a novel LNP that provides a significant advance over conventional LNPs. Our LNP is capable of delivering two types of payloads. The first is an mRNA, a genetic message, that can increase the transcription of a therapeutic gene, Nrf2, that can significantly increase a cell’s protection against oxidative and metabolic stresses. The second is a metabolite, nicotinamide, which has been noted to decline with age and lead to metabolic dysfunction when its levels are low. We believe a dual therapy delivering these two molecules may be an effective treatment for many diseases of aging, including dry AMD for which we currently have no treatments. Furthermore, because of the flexibility and small size of LNPs, if successful there is long-term potential for miniaturization into a form that could be delivered by a less invasive method than eye injection (such as eye drops).

Plans for 2026

New treatments and better ways to deliver treatments for retinal disease are sorely
needed. Here we propose to develop a new nanoparticle that combines a therapeutic
metabolite with a way to deliver genetic code to the eye that could represent a new way
to treat retinal diseases.

The purpose of the project is to develop lipid nanoparticles, which are tiny lipids particles the size of 100-200 nanometers (a nanometer is a billionth of a meter!) which can 1. deliver genetic information for the cell to make a protein that will help protect it against stress and 2. transport a special metabolite called nicotinamide that can recharge an important system that becomes depleted with age. This is a new technology, as most lipid nanoparticle can only transport one type of cargo.

Specific Aims: 1. To test these new nanoparticles on a cultured cell model of
RPE, a central cell in the development age-related macular degeneration
2. To test these new nanoparticles in a mouse model of Age-related Macular Degeneration

Progress in 2025

With RRF funding, Dr. Wu made tremendous strides in understanding how photoreceptor-derived lactate may affect RPE biology to the point where his research had generated sufficient preliminary data to apply for larger sources of funding, and he proposed a new line of inquiry for his project in 2026.

Metabolic modulation of complement in the retinal pigment epithelium

Dr. Wu recently learned that the eye uses glucose (a common sugar) to fuel its activities in a peculiar way. The retina, the light-detecting part of the eye, uses most of the glucose in a process called glycolysis – creating a leftover sugar known as lactate that is shuttled back as fuel for its neighboring tissue, called the retinal pigment epithelium (RPE). Since the retina is the source of the RPE’s lactate, it follows that if the retina becomes sick, the RPE could also become sick. We have evidence that in a common blinding disease known as Age-related Macular Degeneration (AMD), the photoreceptors may become sick. As they make less lactate to share with the neighboring RPE, the RPE may also become sick. One of the ways the RPE can become sick in AMD is through dysregulation of something called the complement system. The complement system is part of the body’s defense against outside invaders (like bacteria), but sometimes instead of destroying bacteria, it also damages the surrounding tissue. In fact, some people who have variations in their complement genes get AMD more frequently than the average population. Dr. Wu found that complement in the RPE may be regulated by lactate metabolism in the eye, and he explored this further and see if those with complement genes putting them at high risk for AMD are more vulnerable to disturbances in lactate metabolism.

Dr. Wu studied whether the rules for lactate regulation of the mitochondria that his laboratory  learned in iPSC-RPE from patients without AMD are the same or different for those from patients with high or low risk variations in genes for AMD or with different types of AMD (for example wet vs dry).  Dr Wu also researched how missing lactate may interfere with the normal importing, metabolizing, and transporting lipids for the retina – a task that is usually an important role of the RPE.

Specific Aims: Aim 1: To understand how lactate regulation of mitochondria changes in the RPE cells of patients with genes that put them at risk for AMD or those with different types of AMD Aim 2: To understand how a loss of lactate can lead to changes in the RPE that reduce the import and metabolism of lipids important for building the retina.

Progress in 2024

Throughout 2024, Dr. Wu’s laboratory was able to continue its studies in the iPSC-RPE model (induced pluripotent stem cell derived RPE cell) – an important model that allows us to grow RPE cells from patients without damaging their eyes.  This allowed the team to study how a patient’s own genetic background may affect different cellular processes.  They learned that a normal metabolite that declines in aging – lactate – can cause specific changes to the structure and function of mitochondria of the RPE.  The mitochondria are the energy factories of the cell, and deterioration of these factories is known to occur as AMD worsens.  This past year, Dr Wu’s team learned that lactate regulation of mitochondria is more complex than previously imagined, as what lactate does can change depending on what other metabolites are present.  In trying to understand what metabolites are present and absent, the lab also learned that the retinas of mice that are missing lactate also end up having fewer lipids than normal, an important building block for retinal cells.

Progress in 2023

During 2023, Dr. Wu’s lab was able to initiate the study of a specialized model of RPE – the iPSC-RPE (induced pluripotent stem cell) in the laboratory. This is an important model that has the advantages of being able to be grown from a patient, thus incorporating their own intrinsic background genetic risks that can be studied. the team learned that a normal metabolite that declines in aging – lactate – may play a central role in helping to maintaining/enhancing the function of mitochondria of the RPE. The Mitochondria are the cellular “energy factories,” of the RPE, and deterioration of these factories is a known occurrence as one’s AMD worsens. Dr. Wu found a particular assay in which he could measure the ability of lactate to enhance mitochondria, called the oxygen consumption rate assay. This is important because better mitochondria function leads to a healthier cell.