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Treatment of a retinal dystrophy, fundus albipunctatus, with oral 9-cis-β-carotene
  1. Ygal Rotenstreich1,4,
  2. Dror Harats2,4,
  3. Aviv Shaish2,
  4. Eran Pras3,4,
  5. Michael Belkin1,4
  1. 1Maurice and Gabriela Goldschleger Eye Research Institute, Sheba Medical Center, Tel-Hashomer, Israel
  2. 2The Bert W Strassburger Lipid Center, Sheba Medical Center, Tel-Hashomer, Israel
  3. 3Department of Ophthalmology, Assaf Harofeh Medical Center, Zerifin, Israel
  4. 4Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  1. Correspondence to Dr Ygal Rotenstreich, Maurice and Gabriela Goldschleger Eye Research Institute, Sheba Medical Center, Tel-Hashomer 52621, Israel; Ygal.rotenstreich{at}


Background Fundus albipunctatus is a retinal dystrophy caused by a mutation in the gene encoding 11-cis-retinol dehydrogenase which delays the recovery of rod photoreceptor cells from light stimulation leading to night blindness. A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal showed an improvement in visual function and structure.

Methods Seven patients with fundus albipunctatus were given a daily food supplement of four capsules containing high-dose 9-cis-β-carotene for 90 days. The subjects were tested before and after treatment by visual field and electroretinogram in both eyes. This non-randomised prospective phase I study was registered at (NCT00478530).

Results All patients showed significant improvements in peripheral visual field (mean deviation improved from −4.77±2.0 to −3.28±2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic b-wave amplitude responses, improved from 197±49 μV to 292±48 μV, p<0.001, t test). No complications or side effects were observed.

Conclusion Oral treatment with 9-cis-β-carotene led to reversal of a human retinal dystrophy. This potential therapy is readily available and should be evaluated in retinal dystrophies of similar mechanisms such as various types of retinitis pigmentosa.

  • Retina
  • vision
  • electrophysiology
  • treatment medical
  • dystrophy

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Vision is dependent on continuous and proper functioning of the retinoid cycle in the retina.1

In rod photoreceptor cells, which are responsible for night vision, the cycle is initiated by the light-induced isomerisation of opsin-bound 11-cis-retinal (‘rhodopsin’) to all-trans-retinal (‘metarhodopsin’).2 In the retinal pigment epithelium, the all-trans-retinal reverts to 11-cis-retinal, through the activity of several enzymes including 11-cis-retinol dehydrogenase.2 The 11-cis-retinal is then delivered from the retinal pigment epithelium to the photoreceptors, where it combines with free opsin and thus restores the sensitivity to light.

Retinoid cycle impairments lead to hitherto untreatable retinal dystrophies and degenerative conditions, such as the various types of retinitis pigmentosa where apoptosis plays a role as well as non-progressive diseases without apoptosis, such as fundus albipunctatus. In retinitis pigmentosa, as well as fundus albipunctatus, these impairments trigger degeneration of photoreceptors owing to accumulation in the retinal pigment epithelium of toxic retinyl esters, as well as of free opsin, which induces further toxic ester production.3–5 Fundus albipunctatus, a form of congenital stationary night blindness, is a non-progressive rod malfunction characterised by distinctive multiple white dots in the fundus.6 This relatively rare eye disease results from a mutation in the gene encoding retinol dehydrogenase 5 (RDH5),7 an essential player in the final restorative step of the retinoid cycle in the retinal pigment epithelium.

A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal, demonstrated structural and electroretinographic evidence of significant improvement in visual function.8 Other experiments showed that a high oral dosage of vitamin A (as retinyl palmitate) reduces the rate of electroretinographic decline in patients with retinitis pigmentosa.9 In the presented study, we attempted to determine whether these results are applicable to patients with fundus albipunctatus.

In this pilot clinical trial, we examined the effects of oral treatment with capsules containing powder rich in 9-cis-β-carotene from the alga Dunaliella bardawil10 on the visual functions of seven patients diagnosed clinically and genetically with fundus albipunctatus.


This non-randomised prospective pilot study was approved by the Sheba Medical Center Institutional Review Committee, and registered at (reg no NCT00478530).

Five men and two women (age range 18–48 years; mean±SD, 37±17) signed their informed consent to participate. All had been clinically diagnosed as having fundus albipunctatus, and genetic analysis had revealed an RDH5 mutation in each case. Smokers were excluded to avoid the possible risk of lung cancer.11

Patients were treated daily for 90 days with a food supplement of four capsules containing β-carotene-rich powder (Nikken Sohonsha, Gifu, Japan). The period of treatment and dosage was determined by previous clinical trials with the tested therapy which showed complete lack of toxicity and clinical benefits.12 Titration confirmed a β-carotene content of 15 mg per capsule, comprising about 50% all-trans-β-carotene and 50% 9-cis-β-carotene.10 Before and immediately after treatment, each patient underwent a full ophthalmological examination, Humphrey visual-field testing (central 24–2 threshold test) and bilateral electroretinographic (ERG) recording (UTAS-E3000; LKC Technologies, Gaithersburg, Maryland) of full-field responses.13 The ERG b-wave responses measured were: (1) cone function for a discrete light stimulus (measured as the response to a single flash of 2.44 cd-s/m2 after background light exposure of 29.63 cd-s/m2 for 10 min); (2) cone function for rapid repeated light stimuli (response to a 30 Hz flickering light of 2.44 cd-s/m2); (3) conventional dark-adapted rod vision (isolated rod responses to a single stimulus of 0.023 cd-s/m2 after dark adaptation for 30 min); (4) late recovery of dark-adapted rod vision (isolated rod responses after 120 min of dark adaptation; (5) rod and cone function (maximal scotopic response to a single stimulus of 2.44 cd-s/m2 after 30 min of dark adaptation); and (6) late recovery of dark-adapted rod and cone vision (response to a single stimulus of 2.44 cd-s/m2 after 120 min of dark adaptation).


All eyes, before and immediately after the trial, had a best-corrected visual acuity of 20/20 (except for the left amblyopic eye of patient 1, which was 20/200). The mean intraocular pressure was 16 mm Hg.

Measured improvements in visual-field mean deviation on treatment termination (mean±SD, excluding the above-mentioned amblyopic eye, in which it could not be measured) ranged from −4.77±2.0 to −3.28±2.28 (figure 1A, p=0.009, t test).

Figure 1

Visual-field scores and scotopic electroretinographic b-wave response amplitudes in the eyes of each patient before and after treatment with 9-cis β-carotene. The visual-field mean deviation scores recorded in (A) show significant improvement after 3 months of treatment (p=0.009). (B) Isolated rod b-wave amplitude responses after 120 min of dark adaptation in the eyes of each patient before (blue column) and immediately after treatment (purple column). Post-treatment electroretinographic b-wave response amplitudes are higher than the pretreatment values in all eyes, and in two patients they exceed the lower limit of normal in both eyes. (C) Maximal scotopic electroretinographic b-wave response amplitudes after 120 min of dark adaptation in the eyes of each patient before (blue column) and 3 months after treatment (purple column). Post-treatment electroretinographic b-wave response amplitudes are higher than the pretreatment values in all eyes except one.

Table 1 presents the visual field and ERG raw data for each patient in each eye. Table 2 records the post-treatment changes (means±SD) in b-wave response amplitudes calculated as percentage changes from baseline, as well as their statistical significance, measured under photopic or scotopic conditions after 30 or 120 min of dark adaptation. After 120 min, the mean isolated rod b-wave amplitude was doubled (132±108%), and the mean maximal scotopic b-wave amplitude increased by 58±56%. Both findings reflect significant improvement in recovery of the rod photo-response.

Table 1

Mean deviation (MD) visual-field score and electroretinographic b-wave response amplitudes*

Table 2

Post-treatment changes in electroretinographic B-wave response amplitudes*

After 120 min of dark adaptation, the isolated rod b-wave amplitude response (shown for each eye individually in figure 1B) was 78±37 μV (mean±SD) before and 171±91 μV immediately after treatment, reflecting a significant mean increase in rod function (p<0.001) and, in both eyes of two patients, rising above lower normal limits. Maximal scotopic b-wave amplitude responses shown for each eye individually in figure 1C, reflecting both cone and rod function, increased, on average, from 197±49 μV before treatment to 292±48 μV immediately after treatment (p<0.001, t test). All patients showed this clinically significant symmetrical improvement in b-wave amplitudes of maximal scotopic and isolated rod responses.

After 120 min of dark adaptation, the mean maximal scotopic a-wave amplitude responses showed a small improvement from 115±27 μV before treatment to 129±36 μV immediately after treatment (17±45%) which was not statistically significant (p=0.334, t test).

Two patients were re-examined 1 year after study termination (figure 2A–C). Figure 2B shows that the ERG isolated rod b-wave amplitude (average of both eyes) of patient 2 (who had opted to continue taking the capsules from 2 months after completing the study) was 134 μV, compared with 42 μV before and 83 μV immediately after the 90-day trial. Patient 3, after 1 year without treatment, achieved an average isolated rod b-wave amplitude of only 69 μV, compared with 96 μV before and 179 μV immediately after the trial. Changes in the patterns of the maximal scotopic b-wave amplitude responses of the two patients were similar (figure 2A,C). The average value for patient 2 after 1 year of treatment was 242 μV, compared with 148 μV before and 263 μV immediately after. Corresponding values for patient 3 were 162, 118 and 298 μV.

Figure 2

Scotopic electroretinographic b-wave response amplitudes of two patients after 1 year. (A) Scotopic electroretinographic b-wave response amplitudes of patient 3 after dark adaptation for 120 min. The isolated rod responses (upper row), representing rod night vision potential, demonstrate significant post-treatment improvement, which however deteriorated to the pretreatment levels after 1 year. Maximal scotopic b-wave response amplitudes (lower row), representing rod and cone night vision also demonstrated significant post-treatment improvement but, at the 1-year follow-up examination, had also reverted to pretreatment levels. (B) Averaged isolated rod b-wave amplitude responses after 120 min of dark adaptation in both eyes of patient 2 (P-2) and of patient 3 (P-3) before and immediately after treatment and 1 year later. At the 1-year follow-up examination, patient 2, who had continued the treatment at his own initiative, showed a further improvement, whereas in patient 3, who had not continued, there was significant deterioration. (C) Maximal scotopic b-wave response amplitudes after 120 min of dark adaptation in both eyes of these patients before and immediately after treatment and 1 year later. At 1 year, patient 2, who had continued the treatment, showed further improvement, whereas the improvement achieved by patient 3 on completion of treatment was not maintained.


In this first demonstration of treatment-induced improvement in psychophysical and electrophysiological parameters of a retinal dystrophy in humans after oral treatment with 9-cis-β-carotene, seven patients with fundus albipunctatus consistently showed significant improvements in retinal function after 90 days of daily oral treatment with a food supplement in the form of high-dose β-carotene capsules. Results were assessed objectively by ERG and subjectively by visual-field testing. On treatment termination, ERG b-wave response amplitudes measured after 120 min of dark adaptation had increased by an average of 132% relative to baseline (p<0.001), indicating that rods regain their function more rapidly than in the absence of treatment. Furthermore, the visual-field mean deviation was also significantly improved after treatment (p=0.009), however, the improvement was less striking it was milder than that of the ERG changes. We assume that magnitude of the improvements in the visual-fields were smaller than that of the ERG changes because the treatment augmented the rods function only, while the visual field represent both the rods and cones. These data are supported by the ERG findings in two patients, 1 year after study completion, showing that the patient who had decided to continue his uptake of high-dose β-carotene maintained the improvement in visual functions, whereas the visual functions of the patient who had ceased treatment at the end of the trial deteriorated to below pretreatment levels. These results are consistent with recently reported significant functional and structural improvements after treatment with 9-cis-retinal in a mouse model of fundus albipunctatus.8 In studies of Rpe65-knockout mice, a model of Leber's congenital amaurosis, 9-cis-retinal induced the production of twice the amount of isorhodopsin (9-cis-retinal and opsin) and doubled the ERG response amplitudes.3 14 The a-wave did not show an improvement as much as the b-wave due to the inherent smaller amplitude and high variability of this measure.

The precise mechanism of the observed beneficial effect has not yet been established. It seems likely, however, that the effect derives from the high availability in the retina of 9-cis-β carotene rather than other components of the food supplement (such as the equally available all-trans form), as can also be inferred from the study cited above.8 Whereas 9-cis-retinal binds to free opsin to generate isorhodopsin, all-trans-retinal does not, and so its presence probably does not influence the therapeutic effect of the cis-retinal form.

In the normal retinoid cycle, 11-cis-retinal regenerates from all-trans-retinal in the retinal pigment epithelium and is subsequently transported back to the photoreceptors, where it combines with the opsin moiety to re-form the light-sensitive rhodopsin molecule. An inborn error of metabolism in the retinoid cycle, such as that caused by mutation of RDH5, causes a deficiency of 11-cis-retinal.6 7 Studies have indicated that orally ingested 9-cis-β-carotene can accumulate in the liver15 and can be assumed to reach the retina, where it combines with opsin to form isorhodopsin, whose visual function differs from that of rhodopsin only in its light absorption peak (494 nm, compared with 502 nm for rhodopsin).16

A possible explanation for the beneficial effects of 9-cis-retinal on rod function in patients with fundus albipunctatus is that 9-cis-retinal is a more stable retinoid than the 11-cis-isomer.2 Its stability would allow larger quantities of rhodopsin to exist in the photoreceptors, thereby probably reducing the activity of the retinoid cycle and resulting in turn in a smaller accumulation of toxic downstream products.8 17 18 Binding of the cis-chromophore to opsin prevents the latter's mislocalisation and preserves photoreceptor structure and function.8 Alternatively, 9-cis-retinal treatment might induce an increase in the endogenous production of 11-cis-retinal, as observed in mice with a different inborn error in the retinoid cycle. This heightened production might result from interaction of 9-cis-retinal with the retinoid X nuclear receptor (RXR).2 19

Physicians contemplating prolonged treatment with β-carotene should bear in mind that it might be toxic, as high vitamin A consumption can reportedly engender photoreceptor degeneration,20 and high doses of retinoids have also been shown to be toxic.21 Nevertheless, neither acute treatment of mice with 9-cis-retinoids nor prolonged treatment for 6 months had any adverse effects, while they restored rod photopigment and rod retinal function.3 This apparent lack of toxicity is consistent with the low levels of toxic agents detected after administration of 9-cis-retinyl esters in other mouse models of inborn errors of metabolism affecting the retinoid cycle.22 Prolonged treatment of mice with other 11-cis-analogues, such as 13-cis-retinal, was not accompanied by retinal toxicity, probably because of their higher rhodopsin stability.17 18

β-Carotene is non-toxic.23 However, as an added precaution, we excluded smokers from the study. Furthermore, the β-carotene capsules used in this study are approved for general use in Japan. Over the last 10 years, while performing clinical trials on hundreds of normal subjects and patients for non-ocular diseases with this food supplement, we have not observed any general or ocular toxic effects, and no blood test analyses for liver, kidney function and blood cells count have shown any toxicity including in this study.10 12

All seven patients in this study showed improved visual functions, as assessed both objectively and subjectively. As far as we are aware, there is no reported treatment demonstrating a significant improvement in retinal functions in patients with retinal dystrophy.24 25 Our results suggest that 9-cis-β-carotene, in the form of the food supplement tested in this pilot trial, is likely to provide at least some benefit in patients with fundus albipunctatus and possibly also other retinal dystrophies, until more radical methods of treatment, including genetic therapies, become available. Moreover, it might be helpful in the future as an adjuvant to genetic therapy, as described for a mouse model of Leber's congenital amaurosis.3 13 A controlled clinical trial is now under way for patients with retinitis pigmentosa to determine whether those successful animal experiments can be recapitulated in people.

Limitations of the present study were its small population, its non-randomised design and the lack of a placebo control group. Further investigations are needed to evaluate the effects of high-dose 9-cis-β-carotene in patients with other retinal dystrophies, such as various types of retinitis pigmentosa and, if the treatment is successful, to establish the optimal dosages and therapeutic regimens.


We thank L Binyaminov, for her accurate and dedicated work on the ERG tests, and T Lubish, for coordinating the study.



  • DH & MB contributed equally to this work.

  • Funding Maratier Fund.

  • Competing interests Tel-Hashomer Medical Center applied for a patent for the ophthalmic uses of the compound tested.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the Sheba Medical Center Institutional Review (Helsinki) Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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