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. 2021 Aug 13;12(8):1241. doi: 10.3390/genes12081241

Table 6.

A summary of the current pharmacological therapeutic studies in ABCA4.

Therapy Mechanism of action Result Reference
Deuterated vitamin A Vitamin A is deuterated at the carbon 20 position which strengthens the bond to the retinaldehyde-PE Schiff base which slows the production of A2E production and also provides more time for the Schiff base to be returned to the visual cycle Abca4 KO Mice:

  • Decreased A2E

  • Decreased ATR dimer

  • Decreased lipofuscin

  • Decreased autofluorescence signal

  • Improvement in electrodiagnostic testing

Phase 1 study in humans

  • Results awaited

 [203,204,205]
RBP4 antagonists Retinol binding protein 4 antagonists inhibit the binding of all-trans-retinol to RBP4 in the serum thus decreasing the transport of all-trans-retinol to the RPE and as a result decreasing bisretinoid production Fenretidine in Abca4 KO:

  • Decreased A2E

  • Decreased AF

A1120 in Abca4 KO:

  • Decreased lipofuscin

  • Possibly better antagonist than fenretidine

 [206]
[207]
Emixustat hydrochloride Emixustat hydrochloride inhibits the RPE65 protein which reduces 11-cis-retinal thus all-trans-retinal and the subsequent A2E accumulation Abca4 KO mice:

  • Decrease A2E

  • Decreased lipofuscin AF

Phase 1 trial

  • “Dose related suppression of rod b wave amplitude recovery post photobleaching”

 [208]
[209]
4-methylpyrazole Inhibits alcohol dehydrogenase Humans

  • No published results on the treated STGD1 patients
Isotretinoin Inhibits 11-cis-retinol dehydrogenase in the RPE thus decreasing 11-cis-retinaldehyde production and rhodopsin regeneration In Abca4 KO

  • Decreased A2E

  • Decreased lipofuscin

  • Delayed dark adaptation

  • Protect photoreceptors from phototoxicity

 [210,211]
Saffron Counteract oxidative damage through the carotenoid constituents crocins and crocetin Shown to be safe in a double-blind placebo-controlled trial [212]
VX-809 Increase expression of ABCA4 protein in cells containing the p.(Ala1038Val) and p. (Gly1961Glu) variants Increased expression of ABCA4 protein in HEK293T cells [213]
Amine containing drugs Sequesters all-trans-retinal by reacting with the aldehyde group and forming an inactive Schiff-base and those that compete with PE thus preventing A2E production Abca4 KOPreserved retinal architecture in treated mice compared to untreated [214]
Ticagrelor Exposure to A2E increases the lysosomal pH which affects degeneration of the photoreceptors. Ticagrlor targets this by inhibiting the P2Y12 receptor to lower the lysosomal pH. Abca4 KO

  • Thicker outer nuclear layer

  • Decreased AF

  • Improved a and b wave responses on EDT

  • Reduced lysosomal pH

  • Higher LAMP1 expression (meaning improved lysosomal function)

 [215,216]
Soraprazan Reversible fast acting inhibitor H+, K+ ATPase that was noted to decrease lipofuscin deposits. Decreased lipofuscin in RPE in treated monkeys and mice [217,218]
Zimura® Target C5 complement pathway to prevent formation of the membrane attack complex thus reducing cell death following activation of the complement pathway by A2E and bistretinoids Results of Phase IIb study awaited [219,220]
Omega 3 fatty acid supplementation Omega 3 fatty acids are thought to be important for general retinal function Trial results awaited NCT03297515
Docosahexaenoic acid (DHA) supplementation DHA normally has a high concentration in the retina and is important towards retinal function A trial showed no improvement in retinal function [221]