From The Editor | April 13, 2022

Opus Genetics, Resilience Partner On Ocular Gene Therapy


By Erin Harris, Editor-In-Chief, Cell & Gene
Follow Me On Twitter @ErinHarris_1

Normal Eye Retina GettyImages-1362506550

Opus Genetics has partnered with Resilience for the development and manufacturing of AAV-based gene therapies for inherited retinal diseases. Opus’ first two programs in LCA target the LCA-5 and RDH12 genes and are licensed from the University of Pennsylvania and based on the work of Opus scientific cofounder, Jean Bennett, M.D., Ph.D., the F.M. Kirby Emeritus Professor of Ophthalmology at the Perelman School of Medicine. Opus’ third program is licensed from Massachusetts Eye and Ear / Harvard and is designed to address NMNAT1-associated retinal degeneration. As these are rare indications, manufacturing efficiently for the scale is the lynchpin of Opus’ success, which this partnership underscores. Ben Yerxa, Ph.D., CEO of the Foundation Fighting Blindness and the Retinal Degeneration Fund and acting CEO of Opus and I caught up to discuss more about Opus’ first three programs as well as Resilience’s role in manufacturing their AAV-based gene therapies.

  1. Explain Opus’ first three programs.

Opus is developing potentially one-time gene therapy treatments delivered subretinally to address mutations in genes that cause inherited retinal diseases, intended to either halt disease progression or rescue visual function.

Our first three programs target different forms of Leber congenital amaurosis (LCA). Opus’s lead program, OPGx-001, is designed to address mutations in the LCA5 gene, which encodes thelebercilin protein. OPGx-001 utilizes an adeno-associated virus 8 (AAV8) vector to precisely deliver a functional LCA5 gene to photoreceptors in the retina.

OPGx-002 focuses on restoring protein expression and halting functional deterioration in patients with retinal dystrophy caused by mutations in the retinal dehydrogenase (RDH12) gene. OPGx-002 also leverages an AAV8 vector, transporting a functional gene to photoreceptors in the retina. OPGx-001 and OPGx-002 are licensed from co-founders of Spark Therapeutics Dr. Jean Bennett and Junwei Sun, of the University of Pennsylvania.

OPGx-003 is a gene augmentation therapy designed to halt functional deterioration in pediatric patients with retinal degenerative disease caused by mutations in the nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) gene. NMNAT1 is an enzyme essential for regeneration of nicotinamide adenine dinucleotide (NAD+) retinal pools, which govern essential cellular processes. OPGx-003 uses NMNAT1 gene therapy for structural rescue of retinal tissue. This program is licensed from the lab of Dr. Eric Pierce, Harvard Medical School and Massachusetts Eye and Ear.

We hope to announce additional programs soon, while building out our earlier stage development work.

  1. From a manufacturing perspective, did Opus consider conducting MFG in house?

Opus is built by and for patients, and given our commitment to putting patients first, we explored and will continue to explore all potential routes to bring these therapies to patients most efficiently. Finding the right partner in Resilience, that understands our unique small-scale approach and can streamline this work, was the right decision for Opus.

The idea behind Opus is not about one program, it’s about building an engine to solve as many degenerative retinal diseases as possible by leveraging scalable and consistent manufacturing processes as much as possible. We see manufacturing as the lynchpin of our success, and scale not in the way you would traditionally think about it in terms of volume of the same drug, but in developing the manufacturing capability and strategically managing the cadence of our clinical timelines to produce therapeutics most efficiently. Where possible, we also intend to utilize the same or similar capsids as another way to streamline process development and overall manufacturing, as well as the same or similar manufacturing process platforms. Our scientific founders, leadership, and relationship with the patient community through our ties to the Foundation Fighting Blindness and the RD Fund enable us to move swiftly in identifying and progressing new therapeutics. At this juncture, working with Resilience is ideal for our development and manufacturing to keep pace. 

  1. Will Opus’ scientists/SMEs work with Resilience during the MFG process?
  • Resilience encourages our partners to participate in person-in-plant activities to support our manufacturing campaigns. As we both have facilities in Research Triangle Park, this will make collaborating on development and manufacturing work easier. On-site presence of our partner can help facilitate collaborative decision making during first-in-human manufacturing campaigns, where process changes might require rapid alignment from both parties.
  • Opus would like to add that we are already working collaboratively with Resilience and have the added benefit from the two organizations being in the same geographic location, and recently hired Brian Leising as Vice President of Manufacturing to lead Opus’ efforts with our partner to manufacture material.
  1. How soon will the AAV-based gene therapies move to the clinic? 

For Opus expects to file an IND and enter the clinic in 2022. We seek to build an engine to bring multiple rare genetic retinal disease therapeutics into the clinic, and our goal is to file at least one IND per year.

  1. From a process development perspective, what did the Resilience team need from Opus up front?

Resilience has developed a manufacturing platform for AAV-based gene therapies. To enable conversion of our manufacturing platform to an Opus-specific process for their ocular-based gene therapies, we needed to understand the quality target product profile (QTPP). Our understanding of the Opus QTPP helps us calibrate specific unit operations to meet analytical targets and specifications, such as the full-to-empty ratio of AAV capsids. The Resilience manufacturing platform has optionality of downstream unit operations to meet the specific full-to-empty target ratio of a product’s QTPP.

  1. What is the future of ocular gene therapy?

Gene therapy for the eye really holds the promise to be on the forefront of gene therapy development and pave the way for other gene therapies. LUXTURNA® (Spark Therapeutics, Philadelphia) was the first approved gene therapy and created by Opus scientific founder Dr. Jean Bennett. There are several advantages of ocular gene therapy vs. other gene therapy areas:

  • small dose required which mitigates the manufacturing yield challenges the industry is facing at this stage; 
  • ability to precisely place the dose in the desired location (subretinally);
  • high levels of immune privilege in the back of the eye; and
  • ability to observe the safety and efficacy readily and non-invasively with various imaging techniques and functional assays.

We’re in a fortunate position in that Opus gene therapies are validated and derisked with strong preclinical evidence supporting their approach and significant work into the programs by our scientific cofounders. We also, where possible, use the same or similar capsids so that we can streamline process development and overall manufacturing.

We are committed to building a new kind of biotech company for the long-term to advance urgently needed treatments for as many of the 260+ related inherited retinal diseases as possible.

In summary, we’re named Opus because our company is bringing together the best instruments of science – the expertise of pioneers in ocular gene therapy, patient voices, committed investors, strong research, and now, a well-suited manufacturing partner – to create important new therapies for patients. This will be our greatest work.