Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease

Abstract

In vivo ophthalmic imaging, electroretinography, and postmortem histological RNA and protein analyses were used to monitor retinal health and function in normal (HbAA) and sickle (HbSS) hemoglobin-producing mice over a one-year period and in additional HbAA and HbSS mice treated with MMF (15 mg/ml) for 5 months. Functional and morphological abnormalities and molecular hallmarks of oxidative stress/inflammation were evident early in HbSS retinas and increased in number and severity with age. Treatment with MMF, a known inducer of Nrf2, induced γ-globin expression and fetal hemoglobin production, improved hematological profiles, and ameliorated SR-related pathology. Innovation and Conclusion: United States Food and Drug Administration-approved formulations in which MMF is the primary bioactive ingredient are currently available to treat multiple sclerosis; such drugs may be effective for treatment of ocular and systemic complications of SCD, and given the pleiotropic effects, other nonsickle-related diseases in which oxidative stress, inflammation, and retinal vascular pathology figure prominently. Antioxid. Redox Signal. 25, 921-935.

Comparison of Neuroprotective Effects of Monomethylfumarate to the Sigma 1 Receptor Ligand (+)-Pentazocine in a Murine Model of Retinitis Pigmentosa

“…39 Finally, a study from the Martin laboratory demonstrated that MMF can attenuate the retinopathy characteristic of sickle cell disease. 40 That study validated the Townes humanized sickle cell disease mouse as a model of Sickle retinopathy and reported that administration of MMF (in drinking water) beginning at 1 month improved the sickle retinopathy as evidenced by functional and structural retinal assessments. It is noteworthy that the onset of detectable retinal alterations in the sickle cell disease model was considerably later (4-7 months) and the severity significantly less than the rapid and fulminant photoreceptor cell loss observed in rd10 mice.…”

Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation: A Promising Emerging Approach with Broad Potential

“…Downstream, it induced CAMKK (Calcium/calmodulin-dependent protein kinase kinase 2) dependent activation of AMPK/SIRT-1 axis which also contributes to reduced inflammation. Several other studies have also reported on the HCAR2 receptor-dependent and independent anti-inflammatory effects of FAE in additional cell types including keratinocytes [31][32][33] and epithelial cells of the retina [34,35].…”

“…Because these initial reports of MMF's potential efficacy in protecting against retinal degeneration were conducted acutely, we decided to evaluate the effect of long-term administration of the compound (5 months administration of 15 mg/ml MMF in drinking water) in the humanized SCD model [34]. Importantly we found via high-pressure liquid chromatography (HPLC) and hematological analyses of peripheral blood that MMF treatment reduced sickle hemoglobin (HbS) content and white blood cell counts, and improved hematocrit, red blood cell number, and hemoglobin concentrations significantly in SCD mice.…”

Developing new pharmacotherapeutic approaches to treating sickle‐cell disease

“…83 The degree to which sickle red cells have deficient defense against oxidative damage has been associated with degree of anaemia. 84 Therefore, studies have been conducted and others are underway to explore the potential utility of anti-oxidant compounds, including arginine, alpha lipoic acid, omega 3 fatty acids, N-acetylcysteine, glutamine, Nrf2 activators, 85-88 haptoglobin, hemopexin 89 and others. Although studies in murine models have looked promising, 90,91 clinical studies have not yet shown definitive benefit to date, although some remain ongoing.…”