Inherited retinal diseases and gene therapies: A pharmaceutical overview

Gene therapy has changed the way we look at diseases that were previously “untreatable.” We have seen amazing advances in the gene therapy category, especially in retina care. Inherited retinal disease is caused by at least a single gene mutation. With more than 300 diseases identified so far, inherited retinal conditions affect approximately 4.5 million people worldwide (Figure 1).¹

Within this therapeutic approach, there are two broad categories for repairing genes: replacement or suppression. In replacement, we are gene-specific in diseases such as Leber congenital amaurosis (LCA) or X-linked retinitis pigmentosa (XLRP). In suppression, we suppress the abnormal function of dominant coding segments such as in autosomal dominant retinitis pigmentosa (ADRP).

Another consideration is the delivery of the gene (Figure 2)², and there are two viruses to chose from: adenovirus and lentivirus. A practitioner must consider potential outcomes for both delivery methods and which approach best serves the patient.

In a similar process, the practitioner must choose between the currently
available modes of delivery for the injections (Figure 3)¹. Subretinal injection is the most common method. The therapeutic is injected into the subretinal space, which necessitates inducing a small retinal detachment. This allows the gene to be delivered directly to the site of the affected cells (retinal pigment epithelial cells and photoreceptors).

Intravitreal injection is, in practice, an easier method for gene delivery. The vector is injected into the vitreous and it must reach the target cell population, but most often, affects the inner retinal layers rather than the RPE cells. This method of injection has potential for a greater immune response.

There are more than 436 studies of ocular gene therapies. For retinal specialists grappling with diseases once thought “untreatable,” this presents a wide range of viable options. The following is a brief overview of retinal diseases that can benefit from a gene therapy approach, and the current ongoing clinical trials.

Retinitis pigmentosa

Retinitis pigmentosa

Retinitis pigmentosa (RP)³ affects one in 4000 individuals, with 15% of that population suffering from XLRP. Rod cell damage from RP leads to peripheral vision loss and nyctalopia. The most commonly affected genes include RHO, USH2A and RPGR; 87 other genes have been identified. Inherited RP is associated with conditions such as Bardet-Biedl and Usher syndrome.

Gene Trials:

• MeiraGTx/Janssen:
  • Phase 1/2 trial(NCT03252847) comparing subretinal injection of different doses (low, intermediate and high) with XLRP patients.
  • LUMEOUS phase 3 (NCT04671433) is currently ongoing.
• AGTC/Beacon Therapeutics:
  • Phase 1/2 SKYLINE (NCT03316560) for XLRP
  • Phase 2/3 study VISTA (NCT04850118) for low/high-dose AGTC0501 with subretinal delivery is currently ongoing.
• ProQR Therapeutics
  • Anti-sense oligonucleotide
  • Phase 1/2 trial (NCT04123626) for ADRP
  • Phase 1/2 trial STELLAR (NCT05176717) for Usher syndrome

Choroidermia

Choroidermia

Choroidermia⁴ is an X-linked retinal disease that affects males (one in 50,000); the inherited disease does also have female carriers. Symptoms can include night blindness (poor dark adaptation), retinal pigment epithelium loss, visual field scotoma (ring) and glare. Macula is preserved until later ages. An electroretinogram shows rod and cone degeneration.

Gene Trials:

• 4D Molecular Therapeutics
  • Phase 1/2 trial (NCT04483440) for mutation in CHM gene; R100 vector intravitreal delivery

Leber congenital amaurosis

Leber congenital amaurosis

Leber congenital amaurosis⁵ is an autosomal recessive disorder. This inherited disease is rare, occurring in two to three out of every 100,000 people. It is characterized by 20/200 or worse
visual acuity, photophobia, nystagmus and sluggish pupils. It is associated with keratoconus, developmental delay, olfactory dysfunction and stereotypical movements.

Gene Trials:

• Spark Therapeutics:
  • Vortigene Neparvovec (Luxturna)
  • First FDA-approved gene therapy for biallelic mutation of RPE65
  • Patients had to navigate obstacle course (multiluminance mobility testing) in phase 3.
  • Treated patients had improved retinal sensitivity and visual fields and were able to pass the multiluminance mobility testing.
  • Visual acuity did not improve and patients who were treated had foveal thinning.
• Editas Medicine:
  • CRISPR/Cas9
  • Removes point mutation in the CEP290 gene
• ProQR Therapeutics:
  • RNA antisense oligonucleotide to prevent CEP290 abnormal splicing
  • Phase 1/2 clinical trial showing improved visual acuity
• Atsena Therapeutics:
  • Phase 1/2 dose escalation study GUCY2D-associated LCA
  • Ongoing

Stargardt disease

Stargardt disease

Stargardt disease^6,7 is typically an autosomal recessive condition. However, dominant genes connected with this disorder do exist. Fatty tissue builds on the macula, and while the vision loss may begin in childhood, some patients do not suffer vision loss until they are adults. The disease is rare (one in 10,000) and caused by a mutation of the ABCA4 gene, which clears the lipofuscin component A2E from photoreceptors. Visual acuity is frequently preserved but can worsen to 20/400.

Gene Trials:

• Sanofi
  • Phase 1/2a study: SAR422459
  • Ongoing
• Alkeus
  • Gildeuretinol (ALK-001)

Achromatopsia

Achromatopsia affects all 3 cone photoreceptors. Patients may suffer from symptoms including poor visual acuity, photophobia, nystagmus and partial or total color blindness.

Gene Trials:

• MeiraGTx/Janssen
  • Phase 1/2 trials for AAV-CNGB3 in adult and paediatric patients
  • Phase 1/2 trials for AAV-CNGA3 in paediatric patients (ages 3-15)
• Applied genetic technologies corporation (AGTC)
  • Phase 1/2 clinical trials for mutations in CNGA3 and CNGB3

References

1. Dalkara D, Sahel JA. Gene therapy for inherited retinal degenerations. C R Biol. 2014 Mar;337(3):185-92. doi: 10.1016/j.crvi.2014.01.002. Epub 2014 Mar 11. PMID: 24702845.

2. Carr ME, Tortella BJ. Emerging and future therapies for hemophilia. J Blood Med. 2015 Sep 3;6:245-55. doi: 10.2147/JBM.S42669. PMID: 26366108; PMCID: PMC4562652.

3. Retinitis pigmentosa image provided by the authors, ©2023 American Academy of Ophthalmology.

4. Choroidermia fundus collage image. MacDonald IM, Hume S, Zhai Y, et al. Choroideremia. 2003 Feb 21 [Updated 2021 Mar 4]. In: Adam MP, Mirzaa GM, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1337/

5. Leber congenital amaurosis image provided by the authors, ©2023 American Academy of Ophthalmology.

6. Stargardt disease image A provided by the authors, ©2023 American Academy of Ophthalmology.

7. Stargardt disease image B provided by the authors, ©2023 American Academy of Ophthalmology.

Laxmi Devisetty, MD | E: laxmiatkuru@gmail.com

Laxmi Devisetty, MD, is a vitreoretinal surgeon and founder/owner of Coastal Retina Institute. She has no financial interest in this topic.

K. Thiran Jayasundera, MD, MS, FACS, FRCSC, FRANZCO | E:thiran@med.umich.edu

K. Thiran Jayasundera, MD, MS, FACS, FRCSC, FRANZCO, is the Paul R. Lichter Professor of Ophthalmic Genetics and the Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan.