FDA OKs AAVantgarde's IND for Stargardt gene therapy trial

AAVantgarde Bio has received FDA clearance for its investigational new drug (IND) application to initiate a first-in-human (FIH) phase 1/2 clinical study on AAVB-039, its Stargardt disease-targeted gene therapy program.

Let’s start with AAVantgarde.

Launched in 2021, the clinical-stage biotechnology company is a spin-off of the Naples, Italy-based Telethon Institute for Genetics and Medicine (TIGEM), an international research institute, and the University of Naples.

Its science: Revolves around the development of two proprietary adeno-associated viral (AAV) vector platforms designed to address AAV vectors’ DNA cargo (transgene) capacity limitations.

• These platforms include:
  • One leveraging DNA recombination (dual hybrid)
    • Disease target: Usher syndrome Type 1B-associated retinitis pigmentosa (Usher1B)
  • One based on protein trans-splicing (AAV intein)
    • Disease target: Stargardt

Take note: This capacity limitation issue is prevalent in such disease-causing genes that exceed the typically capped size of ~4.8 kilobases (kb), including in cases such as the Stargardt-causing ABCA4 gene (which has a size of ~6.8 kb).

Tell me more about these platforms.

For the sake of brevity, we’ll focus on the AAV intein platform utilized by AAVB-039 (which we’ll get to in a moment).

What this encompasses: Two AAV vectors, with each containing an independent expression cassette encoding one of a target protein’s two halves, accompanied by short sequences (known as split iteins).

How it works:

• The platform splits the full-length therapeutic protein in half for each to fit into separate AAV vectors
• Each of those halves is then added to a “split intein” short sequence—a small protein element that controls splicing—essentially fused together
• Following this, both vector halves are co-administered via subretinal injection, with each containing half of the therapeutic protein plus the split-intein sequence (an intein tag, so to speak)
• Once both vector halves encoded with their respective split-intein sequences are inside the same cell, the split-inteins remove themselves to splice the two protein halves together to form one full-length, functional protein

And the resulting effect?

“Protein trans-splicing and full-length protein reconstitution in the retina,” among mice, pigs, and in human retinal organoids, as seen in preclinical studies, according to AAVantgarde.

• “Our data supports the use of split intein-mediate protein trans-splicing in combination with AAV subretinal delivery for gene therapy of inherited blindness due to mutations in large genes (such as in Stargardt),” the company stated.

Keep in mind: That aforementioned data is based on 2019 research published in Science Translational Medicine.

So how does AAVB-039 come into play?

As part of AAVantgarde’s pipeline of AAV gene therapies (and its second clinical program), AAVB-039 is an intra-retinal AAV8-intein-mediated product that targets the ABCA4 gene.

A couple of things to remember:

• AAVs (adeno-associated viruses) are often utilized in gene therapy due to being generally safe and efficacious in delivering genetic material into cells (particularly in humans)
  • Adeno-associated virus serotype 8 (AAV8) is a specific viral vector type used to deliver genetic material to the retina (as it targets photoreceptor cells) to treat retinal disease
• Mutations in the ABCA4 gene lead to the development of Stargardt, referred to as the “ most common inherited retinal disorder caused by mutations in a single gene”

And its mechanism of action?

AAVB-039 uses the proprietary dual AAV intein platform to deliver the full-length ABCA4-protein to address the root cause of Stargardt and enable treatment for all Stargardt patients (regardless of the specific mutation).

As AAVantgarde’s Alberto Auricchio, chief scientific officer and scientific founder, noted, delivering large genes like ABCA4 is a considerable challenge in the ophthalmic (and retinal disease) field.

• “Our approach, validated by rigorous preclinical studies showing quantified high transduction, expression, and long-term safety in multiple relevant models offers a potential therapeutic that addresses the genetic root cause for patients with Stargardt,” he stated.

Now for this upcoming FIH trial.

Dubbed “CELESTE,” the U.S.-based phase 1/2 trial is evaluating the safety, tolerability, and initial efficacy of AAVB-039 among Stargardt patients.

• The company has released no other details on it so far.

Stay tuned for more info to come!

Anything else to know?

Yes! In addition to the CELESTE trial, AAVantgarde is also conducting another study (dubbed “STELLA”) on the gene therapy—designed as a prospective natural history trial (NCT06591806).

• This study is evaluating around 90 Stargardt patients and is already underway at clinical sites across the United States, Europe, and the United Kingdom.

Per Clinical Trials: The trial is expected to conclude in June 2027.