- Pathophysiology of Retinitis Pigmentosa (RP):
- RP is characterized by progressive rod photoreceptor degeneration due to various genetic mutations, followed by secondary cone photoreceptor loss.
- Rods (98% of photoreceptors) consume significant oxygen; their loss reduces oxygen utilization, leading to excess retinal oxygen levels from continued choroidal supply.
- High oxygen levels generate superoxide radicals, causing oxidative stress that damages cone photoreceptors (proteins, lipids, DNA).
- Cone degeneration begins in the mid-periphery, where rod density is high and cone density is low, leading to progressive visual field constriction; the macula (high cone density) is spared until late stages.
- Oxidative Stress Mechanism:
- Excess oxygen produces reactive oxygen species (ROS), including superoxide radicals, which react with nitric oxide to form other damaging ROS.
- Cones are normally equipped to handle oxidative stress but are overwhelmed in RP due to significantly elevated oxygen levels post-rod loss.
- Oxidative stress is greatest in the mid-periphery, explaining the pattern of cone loss from mid-periphery inward and outward, sparing the fovea until late.
- Rationale for NAC in RP:
- NAC is a potent antioxidant that neutralizes ROS, reducing oxidative damage to cone photoreceptors.
- Preclinical Evidence: In RP animal models, NAC prolonged cone survival and function by mitigating oxidative stress.
- Phase 1 Trial:
- Oral NAC (dose escalation, 6 months) in RP patients showed small improvements in cone function (e.g., visual acuity, microperimetry) at higher doses.
- Suggested potential to slow cone degeneration with long-term use.
- NAC Attack Trial: A phase 3 trial designed to assess whether long-term NAC slows cone degeneration and preserves visual function in RP.
- Why NAC?:
- Scientific: NAC is a strong antioxidant, FDA-approved for acetaminophen overdose due to its ability to neutralize potent oxidants (e.g., aldehydes) in the liver.
- Practical: Long history of use with a well-established safety profile, facilitating clinical trial development.
- Unlike gene therapy, NAC is a systemic, oral drug, offering a simpler, scalable approach.
- Clinical Trial Design:
- Targets early-to-mid-stage RP patients (post-rod loss, early cone degeneration) to maximize the chance of detecting a therapeutic effect in a shorter timeframe.
- Uses the maximum tolerated dose (established in phase 1) to balance efficacy and tolerability; gastrointestinal side effects limit higher doses.
- Outcomes focus on objective measures (e.g., visual field, microperimetry) and subjective visual function.
- Safety and Considerations:
- NAC has a good safety profile but requires medical supervision due to potential interactions (e.g., reduces antibiotic efficacy) and variability in over-the-counter formulations.
- Unregulated NAC supplements may contain impurities or inconsistent dosing, posing risks for self-medication.
- Not recommended for off-label use outside clinical trials, especially in early-stage RP, due to unproven long-term efficacy and safety.
- Special Considerations for Late-Stage RP:
- Patients with advanced RP (e.g., hand motion vision) may consider off-label NAC under physician supervision, weighing minimal remaining vision against potential benefits.
- Consultation with a general medical doctor and retina specialist is advised to assess individual risks and monitor for adverse effects.
- Potential Broader Applications:
- Oxidative stress is implicated in other retinal diseases (e.g., age-related macular degeneration), but current focus remains on RP due to trial complexity.
- Hypoxia studies in RP animal models (reduced oxygen exposure) showed cone protection, but systemic hypoxia is impractical for humans due to adaptations (e.g., EPO upregulation).
- Clinical Implications:
- RP progression is slow, allowing patients (especially early-stage) to wait for trial results without significant disadvantage.
- Avoid hyperbaric oxygen therapy in RP patients, as it may exacerbate oxidative stress.
- Differential Diagnosis: RP presents with night blindness, peripheral visual field loss, and bone spicule pigmentation; distinguish from other rod-cone dystrophies or syndromic RP (e.g., Usher syndrome).
- Board-Relevant Takeaways:
- RP is driven by rod loss followed by cone degeneration due to oxidative stress from excess retinal oxygen.
- NAC is a promising antioxidant therapy to slow cone loss in RP, currently under investigation in the NAC Attack trial.
- Recognize the mid-peripheral pattern of visual field loss in RP, with foveal sparing until late stages.
- Counsel patients against self-medication with NAC due to risks of unregulated formulations and unproven efficacy.
- Late-stage RP patients may consider supervised off-label NAC, but early-stage patients should await trial results.
Citation of the Podcast
Maloney, S., Fernandez, B., & Campochiaro, P. (2025). N-Acetylcysteine and retinitis pigmentosa: The NAC Attack trial. BroadEye Podcast.