It's not science fiction – it's advanced personalized medicine!

With support from the Oslo University Hospital Endowment Fund, the Norwegian Association of the Blind and Partially sighted (NABP) and a private donor, what began as an ambitious idea has evolved into groundbreaking interdisciplinary collaboration across healthcare regions and borders.

Rare Inherited Retinal DiseaseRetinitis Pigmentosa (RP) is a rare genetic condition that causes the light-sensitive cells in the retina (photoreceptors) to deteriorate over time. The disease manifests in various forms with differing progressions. Some types lead to severe vision loss and complete blindness at an early age, while others progress more slowly, allowing patients to retain some central vision throughout their lives.

Most individuals with RP experience declining vision in early adulthood. Initial symptoms often include impaired night vision, followed by progressive loss of peripheral vision, resulting in tunnel vision. In advanced stages, color vision and central vision may also be affected. However, most individuals retain a small portion of their central vision.

Gene Therapy Approved

RP has historically been untreatable, but in 2021, the gene therapy Luxturna was approved for reimbursement and use in Norway’s specialist healthcare system. This therapy introduces healthy copies of the RPE65 gene, which is associated with RP type 20 and Leber’s Congenital Amaurosis (LCA) type 10.

Genes are part of our DNA and contain instructions for building proteins essential to cellular function. Genetic disorders arise from "spelling errors" in these instructions, leading to insufficient or defective protein production. By supplying healthy genes, normal protein production and cellular function can be restored.

Since 2021, individuals with these forms of RP have had access to treatments that may prevent vision loss. Currently, Luxturna is the only approved therapy for hereditary retinal diseases globally.

Developing RP11 Therapy

A plan to establish and develop the RP11 project was created in collaboration with national and international experts. Initiated in 2021, the project’s main goal is to develop a treatment for RP type 11 while creating a platform to advance therapies for other inherited retinal conditions.

At the forefront of personalized medicine development, the project is led by a consortium including Oslo University Hospital (OUS), University of Oslo (UiO), Norwegian University of Science and Technology (NTNU), and the startup Zenit Science.

Key contributors include:

• Dr. Josephine Prener Holtan, Senior Consultant at OUS Ullevål and genetic eye disease specialist.
• Prof. Magnar Bjørås, expert in molecular medicine at NTNU and microbiology at UiO and OUS.

The project also involves hospitals in Sweden and Italy, industry partners, and laboratories in the USA, Australia, and Italy.

By targeting RP11, researchers are pushing the boundaries of advanced personalized medicine. These cutting-edge therapies represent a new class of drugs and demonstrate that Norway can conduct world-class research when experts across disciplines collaborate with the biotech industry.

Cross-Border Collaboration

Collaboration is crucial for developing genetic treatments for rare diseases, as patient populations with the same genetic variant are often small. Partnering with Sweden and Italy has been instrumental in enrolling enough participants for natural history studies and clinical trials.

Norway has the technology and knowledge to develop genetic treatments on our own, but this takes a lot of time and resources. The research group therefore leveraged resources by collaborating with PYC Therapeutics in Australia, which was already conducting clinical research on a potential RP11 treatment.

Natural History Study

In 2021, a four-year study began to monitor the disease progression of 26 individuals with RP type 11. This study aims to identify parameters for evaluating treatment efficacy. Participants are from Norway, Sweden, and Italy.

Reprogramming Cells

To investigate how the disease damages retinal cells, patient skin samples were converted into induced pluripotent stem cells (iPSC) in Magnar Bjørås’ lab at UiO. These stem cells can replicate and differentiate into various cell types, including retinal cells.

In NTNU's lab, these iPSCs grow into 3D biological models of the retina (retinal organoids), allowing researchers to study disease mechanisms at the cellular level and test potential treatments without risk to patients. Reprogramming skin cells to form retinal tissue might sound like science fiction, but is in fact just science!

With the help of retinal organoids, researchers are able to describe exactly how RP11 leads to vision loss.

• Which cells are affected first?
• What happens in these cells?
• How long does it take for other cells to be affected?
• When and how should we intervene to stop retinal degeneration with a potential treatment?

Professor Magnar Bjørås and PhD-candidate Jørn-Ove Schjølberg have presented their work with retinal organoids at several global research conferences, and received praise by an international researcher who emphatically stated “Oh, they are beautiful!” upon seeing pictures of the organoids. This is a welcome confirmation that we are on the right path!

Towards RP11 Treatment

With new insights, researchers are closer to achieving their goal of treating RP11. Unlike Luxturna, PYC Therapeutics’ RNA-based therapy targets RNA rather than directly introducing healthy genes.

In short, genes produce RNA which then is spliced together to form proteins. By targeting RNA, we can increase or decrease the amount of available protein to meet the individual needs of patients based on their disease phenotype and pathology.

Individuals with RP11 have one functional copy of the PRPF31 gene producing normal amounts of protein, while the other copy is mutated, resulting in insufficient protein production. PYC discovered that reducing activity in a different gene could increase PRPF31 protein levels, potentially preventing vision loss.

Lab tests using PYC’s RNA therapy on patient-derived retinal organoids have shown promising results, leading to approval for human trials in the USA.

A Bright Future

The RP11 project has in the span of just a few years significantly advanced understanding of disease progression caused by PRPF31 mutations. This knowledge will guide the design of clinical trials, bringing hope that Norwegian patients may soon participate in groundbreaking trials for advanced personalized therapies. It has not yet been decided which hospitals will be selected as trial sites for the upcoming advancement of the clinical trials, but it will be a huge milestone if OUS is chosen and Norwegian RP11 patients for the first time can participate in an interventional study.

Through collaboration between OUS, NTNU, and Zenit Science, Norway is strengthening its expertise in treating inherited retinal diseases, setting the stage for a new era of personalized medicine.