Targeting Inflammation: The Rise of RASP Modulators

Dry eye disease (DED) is a multifactorial, symptomatic disease of the tear film and/or ocular surface and is characterized by tear film instability, hyperosmolarity, neurosensory abnormalities, and ocular surface inflammation and damage. ¹

DED significantly impacts the quality of vision as well as an individual’s quality of life.¹ Symptoms of DED include ocular discomfort, foreign body sensation, irritation, redness, tearing, fluctuating vision, photophobia, and contact lens intolerance.^1,2

Overview of dry eye disease

DED can arise from environmental factors, systemic conditions such as autoimmune diseases, diabetes and thyroid dysfunction, ocular surgery, contact lens wear, medications, nutrition, prolonged screen time, and cosmetics.¹

DED has been traditionally subclassified into aqueous-deficient and evaporative categories; however, many cases have elements of both:¹

In the evaporative form, the predominant cause is meibomian gland dysfunction (MGD), though other contributors include contact lens wear and reduced blink frequency.¹
In the aqueous-deficient subtype, insufficient tear production arises from dysfunction of the lacrimal and accessory lacrimal glands.¹

Age-related changes, systemic medications, autoimmune disease (e.g., Sjögren’s disease), and impairment of neural reflex pathways are common factors leading to reduced aqueous output in aqueous-deficient DED.¹

Common and current DED treatments

Clinically, both over-the-counter and prescription therapies as well as at-home and in-office procedures are available for the management of DED, and a combination of approaches is often necessary to restore and maintain tear film stability, especially in more advanced cases.^1,2

Standard treatment includes lifestyle modifications and tear supplementation; environmental and lifestyle changes such as reduction in screen time, addition of lipid-based supplements, and the addition of humidifiers.^1,2

Additional DED treatment options include:^1,2

Punctal plugs
Tear film stabilizing agents (e.g., perfluorohexyloctane)
Nasal neuromodulators (e.g., varenicline)
Topical neuromodulators (e.g., acoltremon)
Traditional anti-inflammatory agents (e.g., corticosteroids)
Immunomodulators (e.g., lifitegrast, cyclosporine)
Amniotic membranes
Scleral lenses
Treatment of systemic contributors or other ocular surface conditions (e.g., MGD)

Anti-inflammatory therapies such as lifitegrast and cyclosporine-A act by modulating T-cell activity and reducing cytokine-driven inflammation; lifitegrast inhibits the activation of T-cells and the release of inflammatory mediators, which prevents the activation of the inflammatory pathway.^1,2

Cyclosporine-A, in contrast, blocks the inflammatory pathway by acting on activated T-cells to prevent the formation of interleukin-2.³ More recent therapeutic strategies focus on a different approach by intervening to prevent the activation of the inflammatory cascade, aiming to block the formation or release of inflammatory mediators before they trigger tissue damage.³

Introduction to RASP (reactive aldehyde species)

Reactive aldehyde species (RASP), also known as reactive aldehydes, are highly reactive organic molecules generated within the body during conditions of oxidative or metabolic stress.⁴ These molecules bind to proteins, DNA, and membrane lipids, leading to structural damage and triggering inflammatory responses.^4-6

On the ocular surface and throughout the body, commonly produced aldehydes include:^4-6

4-hydroxynonenal (4-HNE)
Malondialdehyde (MDA)
Acrolein

Reactive aldehydes are formed through several pathways. One major source is lipid peroxidation, where reactive oxygen species (ROS) attack polyunsaturated fatty acids.^4,5 Additional contributors include the breakdown of amino acids, sugars, and alcohol as well as environmental exposure to cigarette smoke, overheated cooking oils, and industrial pollutants.^4,5

Excessive accumulation of RASP has harmful consequences, including protein dysfunction, DNA modification, membrane instability, oxidative stress amplification, inflammation, and ultimately, cell death.^4,5 To counterbalance this, the body relies on protective enzymes such as aldehyde dehydrogenases (ALDHs) and glutathione S-transferases (GSTs), which metabolize and detoxify reactive aldehydes.^4,5

Problems arise when RASP production exceeds the capacity of these defense systems, resulting in persistent inflammation that can contribute to or worsen conditions like dry eye disease and ocular surface disorders.^4,5

The link between RASP and ocular inflammation

In DED, tear film instability drives oxidative stress and the generation of ROS.^4-6 ROS induce lipid peroxidation in the tear film, cornea, and conjunctiva, producing RASP.^5,6

Because ocular surface tissues have low levels of detoxifying enzymes such as ALDHs and GSTs, RASP accumulate, affecting inflammatory signaling pathways, including nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPKs), and the NOD-like receptor protein 3 (NLRP3) inflammasome.^5,6

Normally, NF-κB remains bound to its inhibitor, IκB, in the cytoplasm, preventing translocation to the cell nucleus.⁷ Reactive aldehydes activate the IκB kinase complex, leading to IκB degradation, and NF-κB release and translocation to the nucleus. ⁷

This leads to the upregulation of inflammatory cytokines (ex., interleukin 1 beta [IL-1β], interleukin 6 [IL-6], tumor necrosis factor alpha [TNF-α]) and adhesion molecules that recruit immune cells, thereby sustaining ocular surface inflammation.⁷

The MAPK pathway functions as a stress response system; RASP activate MAPKs, which stimulate transcription factors to enhance inflammatory gene expression.⁷ This promotes cytokine and matrix metalloproteinase (MMP) release, epithelial barrier disruption, and apoptosis of corneal and goblet cells—further destabilizing the tear film.⁷

The NLRP3 inflammasome acts as a stress sensor.⁷ In DED, aldehydes prime NLRP3 via NF-κB signaling, while mitochondrial injury provides activation cues.⁷ Activated NLRP3 stimulates caspase-1, which processes interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) into active forms, amplifying inflammation and tissue injury.⁷

Together, the activation of NF-κB, MAPK, and NLRP3 creates a self-perpetuating cycle of immune cell infiltration, epithelial damage, and tear film destabilization that drives chronic inflammation in DED.^5-7

Figure 1: Flowchart outlining how RASP contribute to chronic ocular surface inflammation.

^{Figure 1: Courtesy of Alissa Papan, OD.}

Evidence of elevated RASP in DED

Research has demonstrated significantly elevated levels of RASP, including 4-HNE and MDA, in the tears of patients with non-Sjögren’s DED.^6,7 In one study, individuals with non-Sjögren’s DED exhibited ~10 times higher 4-HNE levels compared to healthy controls.⁶

Furthermore, in patients with Sjögren’s-related DED, conjunctival cells showed a markedly increased presence of 4-HNE, with about 87% of cells staining positive, in contrast to only 27% of conjunctival cells in healthy participants.⁶

These findings suggest that RASP accumulation is closely associated with ocular surface inflammation in both Sjögren’s and non-Sjögren’s dry eye disease.

RASP and allergic conjunctivitis

Allergic conjunctivitis affects up to 40% of the US population.⁸ Similar to dry eye disease, allergic conjunctivitis is associated with oxidative stress on the ocular surface and conjunctival cells, which promotes the formation of RASP and triggers downstream inflammatory pathways.^2,9

This cascade leads to the release of pro-inflammatory cytokines, recruitment of immune cells, and further tissue damage.⁹ Research has shown that therapies targeting and neutralizing RASP can alleviate symptoms of allergic conjunctivitis, including ocular itching, redness, and tearing, suggesting that RASP contribute to the severity of histamine-mediated clinical manifestations.^2,9

Recent research on RASP modulators

RASP modulators are molecules that bind to reactive aldehyde species and neutralize them, preventing these reactive molecules from interacting with cellular components. By doing so, they inhibit activation of key inflammatory pathways, including NF-κB and MAPK, as well as the formation of the NLRP3 inflammasome.^2,5,9-12

Reproxalap (Aldeyra Therapeutics), a first-in-class RASP modulator, targets reactive aldehydes on the ocular surface with the goal of reducing ocular inflammation.^10-12

In the TRANQUILITY study, patients with dry eye disease experienced improvements in symptoms such as discomfort, dryness, and redness after 24-hour QID dosing of Reproxalap.¹¹The study also demonstrated improvements in Schirmer testing following a single dose, with minimal adverse effects reported.¹¹

The INVIGORATE trial evaluated the efficacy of RASP modulation in seasonal allergic conjunctivitis.¹² This quadruple-masked study included 95 participants, with 89 completing the trial; participants had a history of moderate-to-severe allergic conjunctivitis for at least 2 years or an allergen chamber score ≥2.5 for ocular itching and ≥2.0 for ocular redness, or tested positive for ragweed pollen allergy.¹²

Patients receiving Reproxalap ophthalmic solution 0.25% demonstrated significant reductions in ocular redness and itching compared to those receiving the vehicle alone. No severe adverse effects were observed, and the most common side effect was mild ocular irritation upon drop instillation.^10-12

Table 1: Summary of the relevant points of action for the various therapies used to target the inflammatory cascade involved in DED and allergic conjunctivitis.^6-8

Medication/Class	Mechanism of Action	Clinical Use
RASP modulator (Reproxalap)	Neutralizes reactive aldehydes, reducing oxidative stress and preventing the activation of the inflammatory pathway	Dry eye disease and allergic conjunctivitis
Lifitegrast (Xiidra)	Inhibits T-cell activation and cytokine release	Moderate to severe dry eye disease
Cyclosporine-A (Restasis, Cequa)	Inhibits calcineurin and prevents the formation of interleukin-2 (IL-2) and release of cytokines	Dry eye disease and allergic conjunctivitis
Topical antihistamines and mast cell stabilizers	Block histamine-1 (H-1) receptors and stabilize mast cells to prevent the release of histamine	Allergic conjunctivitis (acute-chronic)
Topical corticosteroids	Binds to glucocorticoid receptors, suppressing multiple inflammatory pathways	Moderate to severe dry eye disease (short-term therapy) and allergic conjunctivitis

^{Table 1: Courtesy of Alissa Papan, OD.}

Note: RASP modulators act on the earliest stage of the inflammatory pathway by reducing the oxidative stress that may lead to the activation of the inflammatory pathway, while other medications used to treat ocular surface inflammation act on different arms of the inflammatory pathway.

Clinical implications of Reproxalap for optometry practices

Dry eye disease and allergic conjunctivitis are among the most frequently encountered conditions in eyecare. Reproxalap introduces a novel therapeutic approach as the first medication specifically targeting reactive aldehyde species.

Unlike antihistamines and corticosteroids, which act after inflammatory mediators are released, RASP modulators act upstream, preventing the formation of these inflammatory triggers.^13,14 Clinical trials have demonstrated that RASP modulators can significantly improve symptoms associated with both DED and allergic conjunctivitis, enhancing patient comfort and overall quality of life.^9-12

In practice, RASP modulators may be used alongside other dry eye treatments and conventional anti-allergy drops to provide a more comprehensive and effective management strategy for these ocular surface diseases.

Although there are currently no FDA-approved RASP modulators available, research has shown promising efficacy while maintaining an overall excellent safety profile.¹³

To learn more about how Reproxalap has performed in clinical trials, check out the Glane story: FDA accepts Aldeyra's resubmitted Reproxalap NDA!

Note: The FDA has assigned a Prescription Drug User Fee Act (PDUFA) target action date of December 16, 2025. So stay tuned for updates!

Key takeaways

Reactive aldehydes develop from oxidative and environmental stress to ocular surface tissue
Accumulation of reactive aldehydes can lead to chronic inflammation, cell damage, and cell death
Reproxalap may be used to reduce symptoms of dry eye disease and allergic conjunctivitis
Reproxalap is currently being evaluated by the FDA. Although it has two prior New Drug Application (NDA) submissions, the FDA determined additional data were required to support its efficacy after both previous reviews, and approval is therefore still pending.
However, if Reproxalap does receive FDA approval, prior studies suggest it could be a promising therapy for DED and allergic conjunctivitis.