NAM: The nemesis of glaucoma struck, helping patients stay away from the “thief” of vision

Glaucoma is the leading cause of irreversible blindness worldwide. This disease causes vision loss when the optic nerve and retinal cells are lost. The etiology of the disease is complex, with a wide range of risk factors. Age, race, family history, myopia, cardiovascular disease, diabetes, abnormal blood rheology, etc. are all risk factors for glaucoma. Pathological increase in intraocular pressure (IOP) is The main risk factors for glaucoma. Studies have shown that glaucoma is related to retinal ganglion cell (RGC) apoptosis. The main factors that induce RGC apoptosis are the deprivation of neurotrophic factors, the toxic effects of excitatory amino acids, and the toxic effects of NO. The current clinically available treatment strategies are only aimed at lowering IOP, usually through eye drops or surgery, and not directly at the degeneration of the retina and optic nerve. There is currently no treatment to protect cells from further damage or improve cell function. In clinical practice, many patients still progress to blindness due to the inability to reduce IOP. Therefore, there is an urgent need for neuroprotective strategies that directly target RGC health and reduce the vulnerability to glaucoma-related cell stressors.

NAD+ is an effective mediator of axonal neuroprotection. Recently, the therapeutic potential of regulating NAD+ metabolism has received widespread attention due to its role in aging and neurodegenerative diseases. Recent studies have shown that the level of NAM (NAM is the amide of vitamin B3 and the precursor of NAD+) in the serum of patients with primary open-angle glaucoma (POAG) is reduced, indicating that systemic NAD+ levels may be related to the susceptibility to glaucoma
Researchers supporting this hypothesis measured the RGC function in a mouse model of hereditary glaucoma. When the NAM in the diet increases, the level of retinal NAD+ (the coenzyme nicotinamide adenine dinucleotide that supports the DNA repair system) or NAD is produced. Overexpression of the enzyme (Nmnat1) can provide long-term powerful neuroprotection for RGC, reverse age-related transcriptome changes, and be preserved. These findings support the hypothesis about the potential of NAM supplementation to treat glaucoma.
Recently, the world’s first clinical trial led by the Australian Eye Research Center has shown that NAM can play an important role in preventing nerve cell damage that causes blindness in glaucoma. The results of the trial led by Professor Jonathan Crowston and Dr. Flora Hui from the Australian Eye Research Center were published in “Clinical and Experimental Ophthalmology”.

Part.1

experiment method

Participant flow chart

Participants flow chart (picture source: Clinical & Experimental Ophthalmology)
This study is a prospective, randomized, crossover clinical trial that was conducted in Melbourne, Australia from October 2017 to January 2019. The research schedule is shown in the figure above. The main purpose of the trial is to evaluate the changes in retinal function measured by ERG parameters after 12 weeks of high-dose NAM supplementation compared with placebo.

Of the 94 participants evaluated after the medical record screening, 57 were randomly assigned to the study, of which 49 (86%, 65.5±10.0 years, 39% female) completed the study.

Part.2

The function of retinal ganglion cells improved after NAM treatment

The difference in Vmax ratio between nicotinamide (NAM) and placebo (PL) at week 6 (NAM 6, PL 6) and week 12 (NAM 12, PL 12) showed a significant increase at NAM 12. The internal function of the retina in the NAM group was significantly improved (A). PhNR Vmax (μV) increased significantly at NAM 12. (B) Vmax ratio is expressed as the relative change of nicotinamide (blue) and placebo (pink) from baseline (%) in the 6th and 12th weeks, and it changes significantly at NAM 12 (C). PhNR Vmax also changed significantly at NAM12. (D). After low-dose or high-dose treatment, there was no significant difference between the amplitude of wave a and wave b after treatment with placebo and nicotinamide and the recessive time (photosensitivity) (E, F). There was no significant change in b-wave amplitude and recessive time (bipolar cells) after treatment. (G,H)

Part.3

Changes in parameters of visual field (VF) after treatment

After 12 weeks, there was no difference in the average deviation of VF between the nicotinamide (NAM) and placebo (PL) groups at the 6th and 12th weeks (A). Similarly, when using NAM, the PSD will only decrease slightly (B). Compared with placebo, a greater proportion of participants after high-dose NAM had a MD increase of ≥1dB from baseline, while patients who received high-dose NAM had a decrease of ≥1dB compared with placebo (C). For PSD, this is not obvious. After NAM and PL, the increase or decrease of a similar proportion of participants is ≥1 dB(D). For placebo and NAM treatment, there was a moderately positive correlation between the changes in PhNR Vmax and VF MD at 12 weeks (E, F). There is a moderately positive correlation (G, H) between PhNR Vmax and VF MLS and placebo and NAM.

Part.4

Conclusion and discussion

The data provided by the researchers showed that in glaucoma patients with increased IOP, after 12 weeks of supplementation, NAM can lead to early improvements in the internal function of the retina. Overall, NAM is well tolerated, with an adherence rate> 94%. As POAG patients have been shown to have reduced systemic NAM levels, the use of NAM in combination with existing IOP reduction strategies may be a convenient, safe, and cost-effective treatment.
The trial recruited glaucoma patients who had already received good IOP control. Since oral NAM treatment cannot change IOP, the observed effect of NAM on the internal function of the retina is unlikely to be mediated by changes in IOP. Instead, the metabolism salvage of RGCs is a hypothetical mechanism of action. The researchers hypothesized that NAM supplementation may benefit eyes with elevated IOP, and that elevated IOP is related to increased metabolic stress and dysfunction of RGCs. The dose of NAM used in the study was derived from clinical trial experience. Due to differences in pharmacokinetics and pharmacodynamics between people, this dose may not be the most ideal. There is no evidence of residual effects, which may be due to the relatively short plasma half-life of NAM in humans (3.5 hours after the 25 mg/kg dose).
In short, it is concluded through experiments that oral NAM supplementation therapy can improve internal retinal function early and measurably in glaucoma patients who have received IOP reduction. Researchers said that it is not yet possible to say what effect supplementation of NAM may have on the quality of life of glaucoma patients. Therefore, it is now necessary to conduct a wider range of long-term NAM treatment clinical trials to explore whether these effects continue and can slow down the development of glaucoma. development of.
Medicilon’s pre-clinical ophthalmology platform has a special intra-ocular drug delivery technology and is equipped with an advanced ophthalmic surgical microscope. In addition to conventional eye drops and ointment administration, it can also be used to treat rabbits, dogs, small pigs and non- Animal species such as human primates achieve unique fine drug delivery.
Our unique delivery methods include: subretinal injection; choroidal injection; intravitreal injection. In addition, there are also complete instrument detection systems, such as Heidelberg laser ophthalmology diagnostic equipment, Roland ocular electrophysiological diagnosis system, fundus photography equipment (color fundus photography), etc., Medicilon’s complete eye detection system also includes configuration digital Slit lamp of camera system, tonometer, fundus laser instrument, indirect ophthalmoscope, ophthalmic surgery microscope, etc.
Medicilon also has a variety of animal models of eye diseases, including conjunctival tissue proliferation and NV, diabetic retinopathy (DR), choroidal neovascularization (CNV) and subretinal fibrosis , Corneal neovascularization (Corneal NV), retinal neovascularization, acute ocular inflammation model, dry eye, etc. Medicilon will continue to pay attention to the progress of this research and contribute to the development of the treatment of eye diseases.
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