CRISPR gene editing may prevent early-onset vision loss

Research published in The New England Journal of Medicine investigated the use of clustered regularly interspaced short palindromic repeats (CRISPR)-gene therapy for correcting a form of inherited retinal degeneration (IRD) that leads to early-onset vision loss.

Let’s start with some background.

First things first: Pathogenic variants of the gene-encoding centrosomal protein 290 (CEP290) are known to cause CEP290-associated IRD.

• Why this is important: Associated with visual impairment during the first 10 years of life, the pathogenic variant (intron 26 of CEP290, or just “IVS26” for short) in this protein is also the most common cause of genetic childhood blindness.
  • In other words: Leber’s congenital amaurosis (LCA)
    • Note: The most common variant linked to CEP290 has been found to be present in up to 77% of patients with LCA.

Is there any treatment for this form of IRD?

Unfortunately, no. The current standard of care involves interventions such the use of:

• Glasses
• Magnifiers
• Canes
• Braille
• Home modifications

And how is this disease characterized?

Internally, it’s noted by “disorganized outer segments of rod and cone photoreceptors and early death of rods in the mid-peripheral retina,” with the cones retained, according to investigators.

Plus: Both the optic nerves and occipital cortices are typically structurally intact in spite of a reduced input from the rod and cone receptors.

• Significance: This could potentially lead to intervention and targeting of any photoreceptors that were spared in order to restore vision.

So what’s being proposed for treatment?

That’s where a new technology involving an EDIT-101 injection comes into play.

What it is: A gene-editing therapy—CRISPR/CRISPR-associated protein 9 (Cas9), to be exact—designed to permanently remove the CEP290 IVS26 variant.

Alrighty, now talk about this study.

Investigators conducted an open-label, single-ascending dose phase 1/2 study identified as the BRILLIANCE study (NCT03872479) that analyzed the safety, tolerability, and efficacy of single, escalating doses of EDIT-101 when administered via subretinal injection.

The participants: Adult and pediatric patients (aged 3+) diagnosed with LCA10 caused by the CEP290 IVS26 variant. See here for complete criteria.

Note: The study was led by principal investigator Eric Pierce, MD, PhD, director of the Berman-Gund Laboratory for the Study of Retinal Degenerations at Massachusetts (Mass) Eye and Ear, as well as director of the Ocular Genomics Institute at Harvard Medical School.

How was it set up?

Participants were assigned to one of five cohorts to receive a single dose of the EDIT-101 gene in ascending order of dosages (three in total):

• Adults (low dose)
  • 6×1011 vector genomes [vg] per mL
• Adults (middle dose)
  • 1×1012 vg per mL
• Adults (high dose)
  • 3×1012 vg per mL
• Pediatrics (middle dose)
  • 1×1012 vg per mL
• Pediatrics (high dose)
  • 3×1012 vg per mL

And what was measured?

Measured at 1 year following subretinal injection, the study evaluated three main outcomes:

• Adverse events (AEs) related to EDIT-101
• Participants experiencing procedural-related AEs
• Dose-limiting toxicities

Among the 16 secondary outcomes (also measured at 1 year), the following were assessed:

• Maximum tolerated dose based on dose-limiting toxicities
• Mobility test
• LogMAR measurement of best-corrected visual acuity (BCVA)
• Change from baseline in:
  • Quality of life (QoL) score for:
    • Age 8 to < 18
    • Age >18 if BCVA was worse than 1.0 logMAR in both eyes
    • Age >18 if BCVA was 1.0 logMAR or better in both eyes
  • Pupil response
  • Dark adapted visual sensitivity via full-field light sensitivity threshold
  • Macula thickness

See here for the complete list.

Now to the data… how many participants were dosed?

EDIT-101 doses were injected into a total of 12 adults (aged 17 to 63; average age of 37) and two children (aged 9 and 14), broken down into the following:

• Adults
  • Low dose (n = 2)
  • Medium dose (n = 5)
  • High dose (n = 5)
• Pediatrics
  • Medium dose (n = 2)

And the findings?

The data found that, at baseline, the median BCVA in the study eye was 2.4 log10 of the minimum angle of resolution (range: 3.9 to 0.6).

Further: Because most participants had a severe loss of VA at below 1.6 logMAR, VA could only be tested via the Berkeley Rudimentary Vision Test (which extends the range of VA measurement beyond the limits of letter characters).

• For all patients: At least 3 log units elevated spectral sensitivity, rod function was undetectable
  • Also: Photoreceptor layer thickness was noted within normal limits (for most patients).

Did any AEs develop?

No serious AEs that were related to the treatment/procedure—in fact, most AEs were mild while an estimated 20% were moderate and only 40% were treatment-related.

Plus, there were no recorded dose-limiting toxicities.

How about vision improvements?

A total of six participants had a “meaningful improvement from baseline in cone-mediated vision,” according to the study authors.

• Of those: Five had improvement in at least one of the 16 secondary outcomes.

Meaningful improvements were also noted in 64% (nine) patients from baseline in:

• BCVA
• Sensitivity to red light
• Score on the mobility test

Plus, an additional six participants had a meaningful improvement from baseline in vision-related QoL score.

So overall?

Out of the 14 participants, 11 demonstrated some improvements in vision and QoL measures.

And the authors’ conclusions?

The study authors concluded that the study’s findings support further research of in vivo CRISPR-Cas9 gene editing” for the treatment of IRD as a result of the CEP290 IVS26 variant and other potential genetic causes.

Go on…

“This research demonstrates that CRISPR gene therapy for inherited vision loss is worth continued pursuit in research and clinical trials,” stated Dr. Pierce. “While more research is needed to determine who may benefit most, we consider the early results promising.”

What’s the significance?

The phase 1/2 is noted as including the first patient (ever) to receive a CRISPR-based investigational medical directly inside the body and focused on safety with efficacy as a secondary analysis, according to Mass Eye and Ear.

SriniVas Sadda, MD, president of the Association for Research and Vision in Ophthalmology (ARVO), noted the historical significance of the study's findings.

"This is a landmark step forward, because gene therapy approaches which simply insert a functional copy of gene into a cell will be unlikely to be effective for autosomal dominant inherited retinal diseases," he wrote to Glance. "Gene editing theoretically allows a defective copy of the gene to be removed which may make treatment for these autosomal dominantly-inherited diseases to be feasible.

So what’s next?

Investigators are now looking to collaborate with new commercial partners (along with Editas, their original partner) to conduct additional studies on this form of gene editing.

More specifically:

• Examining the ideal EDIT-101 dosing
• Determining if the therapy is more effective in a particular age group
• Establishing endpoints to measure the impact of improved cone function on daily activities

As far as specific diseases to target, Dr. Sadda noted the following autosomal dominantly (AD) inherited diseases as having potential:

• Alzheimer's disease
• Retinitis pigmentosa
• Late-onset retinal dystrophy
  Best’s disease