Article

Update on Stargardt disease

The exploration of many new avenues of therapeutic intervention offers promise.

Stargardt disease is the most prevalent form of inherited macular degeneration in both adults and children. Also known as Stargardt macular dystrophy or juvenile macular dystrophy, Stargardt disease (STGD1) has an estimated prevalence of 1 in 10,0001,2 and is transmitted in an autosomal recessive manner due to mutations in the ABCA4 gene.3-6 Patients may present with bilateral visual complaints of central scotoma, vision loss or color vision changes and are found to have central atrophy and characteristic yellow pisciform (fish-shaped) flecks in the macula.

STGD1 is, clinically and genetically, very heterogeneous. Onset is most commonly in childhood (hence the name juvenile macular dystrophy), but a second peak of onset also occurs in early adulthood. More recently, it has been found that forms of STGD1 may not present until later adulthood and therefore may be confused with AMD, with later onset associated with generally better prognosis.7-10 Significant variability exists between individuals, even between family members with the same known ABCA4 mutation, suggesting environmental and other genetic modifiers affect clinical disease. Over time, patients experience a progressive loss of vision associated with loss of retinal function and macular structure.

There are no proven treatments for STGD1, but several promising therapeutic interventions are currently in clinical trials. Here, I’ll describe those interventions and explain current diagnostic techniques for this disease.

DIAGNOSTICS

Clinical exam findings

Classical clinical findings of STGD1 include the presence of irregular yellowish flecks, sometimes described as pisciform, at the level of the retinal pigment epithelium (RPE) in the macula that can extend out into the periphery (Figure 1, page 26). These flecks are variable in shape, size and distribution and are created by excessive accumulation of lipofuscin in the RPE. Macular atrophy, macular pigment mottling and macula depigmentation can also develop. Initially, clinical exam may show a normal fundus or just mild foveal pigment mottling changes.11 Also, up to one third of children may not initially present with flecks.10

Figure 1. Color fundus photo showing typical yellow-white flecks that extend into the midperiphery of a patient with STGD1.

Visual acuity can be highly variable, with vision changes in juvenile patients more likely to result in early severe vision loss10 and BCVA worse than 20/400 later in life.12 Classic flecks within the macula may not be present initially but develop and progress later in life.10 Over time, these flecks may also fade and be replaced by atrophy. Although rare, patients with STGD1 can also develop choroidal neovascular membranes.

Retinal imaging

Ocular imaging techniques can provide further information useful in diagnosis, characterization and monitoring of STGD1. Fluorescein angiography (FA) in STGD1 can show the classic “dark choroid,” with reduced fluorescence from the choroid due to blockage by lipofuscin in the RPE, although this is not present in all patients.13 Fundus autofluorescence (FAF), which can be done quickly and noninvasively in the clinic, has largely replaced FA in the assessment of STGD1. FAF shows hyperfluorescence in lipofuscin-laden areas, sometimes before they are apparent clinically, and hypofluorescence in areas of macular atrophy due to loss of RPE (Figure 2).14 Subtypes of FAF may help predict disease progression.15 Also, spectral domain optical coherence tomography (SD-OCT) can help show alterations of outer retinal structure in the macula.11 Other research imaging modalities, such as adaptive optics, have given new insights to cellular structural changes at the level of the photoreceptor mosaic in STGD1.16,17

Figure 2. Fundus autofluorescence image corresponding to color image from Figure 1 showing flecks within the macula with both increased and decreased autofluorescence.

Genetics

STGD1 is inherited in an autosomal recessive manner due to mutations in the ABCA4 gene located on the short arm of chromosome 1p21-22, with an estimated carrier prevalence as high as one in 10.18 Over 1,000 different mutations within this gene are known to be associated with STGD1.6 The ABCA4 gene encodes the ATP-binding cassette, subfamily A, member 4 transporter, which has been localized to the rims of outer segment discs of both rod and cone photoreceptor cells.19-21 This transporter is involved in the active transport of retinoids from photoreceptors to the RPE, making it an important component of photoreceptor hemostasis. Mutations in ABCA4 are associated with accumulation of N-retinylidene-N-retinylethanolamine (A2E), which is a major fluorophore of lipofuscin.21 Over time, the accumulation of excess lipofuscin leads to atrophy of the RPE and photoreceptor degeneration, resulting in progressive vision loss.19

It is also important to note that autosomal dominant forms of Stargardt-like macular dystrophy can develop from mutations in ELOVL4, PROM-1 and PRPH2/RDS genes. Patients who present with central vision loss can have clinical exam findings of macular atrophy and/or retinal flecks indistinguishable from ABCA4 gene-related Stargardt disease. A family history showing autosomal dominant inheritance is helpful to distinguish these from the ABCA4-related STGD1.22-24

TREATMENTS

Emerging therapeutic interventions

Many novel therapeutic approaches to slowing or halting degeneration are emerging. Early phase clinical treatment trials are currently ongoing for medical therapies, gene therapy and stem cell therapies. Concurrent to this, the multicenter Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) studies are occurring. Progstar, sponsored by the Foundation Fighting Blindness, is designed to help characterize the natural history of progression of retinal changes and to explore clinical trial endpoints, such as SD-OCT, FAF, microperimetry and visual acuity changes in STGD1.11

ALK-001 (Alkeus Pharmaceuticals Inc.) is currently in a Phase 2 multicenter clinical trial for the treatment of STGD1 (ClinicalTrials.gov identifier: NCT02402660). ALK-001 is a deuterated form of vitamin A taken orally once a day. It works to slow the rate of vitamin A dimerization in the retina, impeding the subsequent formation of A2E and lipofuscin without other adverse effects on retinal function.25,26 A Phase 1 clinical trial with ALK-001 with healthy volunteers completed in 2015 with no safety concerns. The Phase 2 trial is estimated to be completed in 2018.

Emixustat hydrochloride (Acucela, Inc.) is an oral molecule that works as a reversible antagonist of RPE-65. It works to slow the visual cycle by inhibiting RPE-65 and reducing the accumulation of toxic retinal byproducts, such as A2E. A multicenter Phase 2a trial evaluating its use in treatment of macular atrophy secondary to Stargardt completed in December (ClinicalTrials.gov identifier: NCT03033108). Results are pending.

Avacincaptad pegol (Zimura; Ophthotech Corp), a complement C5 inhibitor given by intravitreal injection, has just begun enrolling a Phase 2a multicenter clinical trial to explore the safety and efficacy in treatment of STGD1 (ClinicalTrials.gov identifier: NCT03364153). Results are anticipated in 2020.

Gene therapy

Dysfunction of the ABCA4 gene results in the majority of retinal dysfunction and loss in STGD1. Therefore, replacement of this gene with gene therapy is a logical approach to halting progression and preventing further loss of retinal tissue. Most ongoing ocular gene therapy trials use adeno-associated viral (AAV) vectors for delivery of genes into ocular tissues; however, AAV vectors are limited to carrying a gene around 4.7 kb in weight. The ABCA4 gene is around 7 kb;27 therefore, current trials use lentivirus vectors, which can package larger genes with a capacity of 8-10 kb, for delivery of gene product to cells. Both AAV vectors and lentivirus vectors can transduce non-dividing cells, but AAV are nonintegrating while lentivirus can integrate into the host cell genome.

SAR422459 (Sanofi; formerly known as Stargen) is a lentivirus vector gene therapy carrying the ABCA4 gene for the treatment of STGD1 (ClinicalTrials.gov identifier: NCT01367444). It is administered subretinally after a pars plana vitrectomy. The primary objective of the trial is to evaluate safety and tolerability of SAR422459, and the secondary objective is to evaluate biologic activity. The trial is a dose-escalation study, with a review by a data and safety monitoring board after each cohort enrolls. The plan is to continue enrollment of the youngest patients with the most rapid progression of disease (ages 6 to 26 years). To date, there are no safety concerns identified. This trial is ongoing.

Stem cell treatments

Severe vision loss in STGD1 is due to central atrophy of the macula. It is believed that RPE cell dysfunction and loss precedes photoreceptor dysfunction and loss. Thus, regeneration of the RPE with stem cells holds potential for preventing further vision loss in STGD1.

A Phase 1/2 stem cell clinical trial using human embryonic stem cell-derived RPE cells transplanted subretinally into patients with severe end-stage STGD1 (ClinicalTrials.gov identifier: NCT01345006) has been undertaken.28 No serious adverse safety events related to the transplanted cells have occurred. Of the seven patients with one-year visual assessment, three had improved vision, three had stable vision and one had vision loss.28 However, given the extensive atrophy of the outer retina that can occur in STGD1, replacement of RPE alone may be not be sufficient and photoreceptor cells may also need to be replaced.

CONCLUSION

While Stargardt disease can result in devastating vision loss, sometimes at an early age, many new avenues of therapeutic interventions are being explored to slow and halt disease, and, ultimately, potentially reverse vision loss. For the thousands of individuals affected by STGD1 and for the providers who manage their care, it is a very hopeful time. OM

REFERENCES

  1. Michaelides M, Hunt DM, Moore AT. The genetics of inherited macular dystrophies. J Med Genet. 2003;40:641-650.
  2. Stone EM, Andorf JL, Whitmore SS, et al. Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease. Ophthalmology. 2017;124: 1314-1331.
  3. Allikmets R, Shroyer NF, Singh N, et al. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science. 1997;277:1805-1807.
  4. Fujinami K, Zernant J, Chana RK, et al. ABCA4 gene screening by next-generation sequencing in a British cohort. Invest Ophthalmol Vis Sci. 2013. 54(10): p. 6662-6674.
  5. Zernant J, Schubert C, Im KM, et al. Analysis of the ABCA4 gene by next-generation sequencing. Invest Ophthalmol Vis Sci. 2011:52:8479-8487.
  6. Zernant J, Xie YA, Ayuso C, et al. Analysis of the ABCA4 genomic locus in Stargardt disease. Hum Mol Genet. 2014;23:6797-6806.
  7. Lambertus S, Lindner M, Bax NM, et al. Progression of Late-Onset Stargardt Disease. Invest Ophthalmol Vis Sci. 2016;57:5186-5191.
  8. Lambertus S, van Huet RA, Bax NM, et al. Early-onset stargardt disease: phenotypic and genotypic characteristics. Ophthalmology. 2015;122:335-344.
  9. Fujinami K, Lois N, Mukherjee R, et al. A longitudinal study of Stargardt disease: quantitative assessment of fundus autofluorescence, progression, and genotype correlations. Invest Ophthalmol Vis Sci. 2013;54:8181-8190.
  10. Fujinami K, Zerant J, Chana RK, et al. Clinical and molecular characteristics of childhood-onset Stargardt disease. Ophthalmology. 2015;122:326-334.
  11. Strauss RW, Ho A, Muñoz B, et al. The Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Studies: Design and Baseline Characteristics: ProgStar Report No. 1. Ophthalmology. 2016;123: 817-828.
  12. Collison FT, Fishman GA. VISUAL ACUITY IN PATIENTS WITH STARGARDT DISEASE AFTER AGE 40. Retina. 2017, Oct 24: published ahead of print.
  13. Fishman GA, Stone EM, Grover S, et al., Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene. Arch Ophthalmol. 1999; 117:504-510.
  14. Strauss RW, Muñoz B, Ho A, et al. Incidence of Atrophic Lesions in Stargardt Disease in the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) Study: Report No. 5. JAMA Ophthalmol. 2017; 135:687-695.
  15. Strauss RW, Muñoz B, Ho A, et al. Progression of Stargardt Disease as Determined by Fundus Autofluorescence in the Retrospective Progression of Stargardt Disease Study (ProgStar Report No. 9). JAMA Ophthalmol. 2017;135:1232-1241.
  16. Razeen MM, Cooper RF, Langlo CS, et al. Correlating Photoreceptor Mosaic Structure to Clinical Findings in Stargardt Disease. Transl Vis Sci Technol. 2016;5:6.
  17. Chen Y, Ratnam K, Sundquist SM, et al. Cone photoreceptor abnormalities correlate with vision loss in patients with Stargardt disease. Invest Ophthalmol Vis Sci. 2011;52:3281-3292.
  18. Jaakson K, Zernat J, Külm M, et al. Genotyping microarray (gene chip) for the ABCR (ABCA4) gene. Hum Mutat. 2003;22:395-403.
  19. Tsybovsky Y, Molday RS, Palczewski K. The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. Adv Exp Med Biol. 2010;703:105-125.
  20. Tsybovsky Y, Wang B, Quazi F, Molday RS, Palczewski K. Posttranslational modifications of the photoreceptor-specific ABC transporter ABCA4. Biochemistry. 2011;50:6855-6866.
  21. Cideciyan AV, Aleman TS, Swider M, et al. Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence. Hum Mol Genet. 2004;13:525-534.
  22. Boon CJ, van Schooneveld MJ, den Hollander AI, et al. Mutations in the peripherin/RDS gene are an important cause of multifocal pattern dystrophy simulating STGD1/fundus flavimaculatus. Br J Ophthalmol. 2007;91:1504-1511.
  23. Kim JM, Lee C, Lee GI, et al. Identification of the PROM1 Mutation p.R373C in a Korean Patient With Autosomal Dominant Stargardt-like Macular Dystrophy. Ann Lab Med. 2017;37:536-539.
  24. Palejwala NV, Gale MJ, Clark RF, et al. Insights into autosomal dominant stargardt-like macular dystrophy through multimodality diagnostic imaging. Retina. 2016;36:119-130.
  25. Washington I, Saad L. The Rate of Vitamin A Dimerization in Lipofuscinogenesis, Fundus Autofluorescence, Retinal Senescence and Degeneration. Adv Exp Med Biol. 2016;854:347-353.
  26. Charbel Issa P, Barnhard AR, Herrmann P, Washington I, MacLaren RE. Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization. Proc Natl Acad Sci U S A. 2015;112:8415-8420.
  27. Auricchio A., Trapani I, Allikmets R. Gene Therapy of ABCA4-Associated Diseases. Cold Spring Harb Perspect Med. 2015;5:a017301.
  28. Schwartz SD, Regillo CD, Lam BL, et al. Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies. Lancet. 2015;385:509-516.

About the Author