Future therapies for RP

There is currently no cure for most forms of retinitis pigmentosa, but RP research has expanded significantly.

Researchers are working on treatments that address different stages and causes of the condition. Some aim to correct the genetic problem that causes retinal cells to deteriorate. Others are designed to protect the cells that remain or restore useful vision after many photoreceptors have already been lost.

These approaches are at very different stages. Some are being tested in large clinical trials, while others have only been studied in cells or animals. A promising laboratory result does not necessarily mean that a treatment is close to becoming available.

LUXTURNA is an FDA-approved gene therapy (definition: A treatment that delivers a working copy of a gene into cells to take over for a copy that isn't functioning properly.) for certain people with an inherited retinal disease caused by disease-causing variants in both copies of the RPE65 gene.

The treatment delivers a working copy of the RPE65 gene directly beneath the retina. A person must have confirmed genetic results and enough viable retinal cells remaining to be eligible.

LUXTURNA was an important milestone because it showed that an inherited retinal disease could be treated by addressing its genetic cause. However, it does not treat RP caused by other genes.

Most future RP therapies are designed around one of three goals:

• Slow or prevent further damage by protecting retinal cells that are still working
• Address the underlying cause by replacing, repairing, or changing how a gene is used
• Restore useful vision by replacing lost cells or helping other cells respond to light

Which approach may be relevant depends partly on the gene involved and how much functioning retina remains.

Gene replacement therapy delivers a working copy of a gene to retinal cells. The new copy does not remove the original variant. Instead, it gives the cells instructions they can use to produce a working protein.

This approach is generally most suitable when RP is caused by a gene that is not producing enough functional protein. Because each therapy is usually designed around a particular gene, separate treatments may be needed for different genetic forms of RP.

Researchers are studying gene therapies for several RP genes, including forms associated with RPGR, RHO, PDE6A, and PDE6B. Other approaches, sometimes called modifier gene therapies, are being studied with the goal of helping people with more than one genetic form of RP. Gene therapies for RP range from early research to late-stage clinical trials.

Gene editing aims to change the DNA already inside a person's cells. Technologies such as CRISPR (definition: A gene-editing technology that can find and change a specific, targeted spot in a cell's DNA.) can be designed to remove, disable, or correct a harmful genetic instruction.

This may be useful for dominant forms of RP, in which an altered gene produces a protein that actively interferes with the retina. In these cases, simply adding another working copy of the gene may not be enough.

Researchers have used gene editing to correct an RP-causing RHO variant in a mouse model and improve retinal structure and function. This work remains preclinical (definition: Research done in cells or animals, before a treatment is considered ready to be studied in people.) and must undergo further testing before it could become a treatment for patients.

Genes contain instructions for making proteins, but those instructions first pass through a molecule called RNA. RNA-based treatments aim to change how those instructions are read or processed without permanently changing the DNA.

Depending on the genetic problem, an RNA treatment may:

• Help the cell skip over a harmful section of genetic instructions
• Reduce the production of a damaging protein
• Allow the cell to produce a more useful version of a protein

These treatments can be highly specific. A therapy may apply only to people with a particular variant or a particular section of a gene. RNA-based treatments have entered clinical development for inherited retinal conditions associated with genes including USH2A.

Not every treatment under study is designed around one gene. Researchers are also studying treatments that act on processes shared by many forms of RP.

When rod cells deteriorate, the environment inside the retina changes. Oxidative stress, inflammation, and other forms of cell stress may contribute to the later loss of cone cells. Neuroprotective (definition: Describes a treatment designed to protect cells — here, retinal cells — from damage and help them survive longer, rather than replacing or repairing them.) treatments aim to reduce that damage and keep the remaining photoreceptors working for longer.

One example is N-acetylcysteine, or NAC, an antioxidant being evaluated in a Phase 3 clinical trial to determine whether it can safely slow vision loss in people with RP. NAC is still investigational for RP and should not be used for this purpose without medical guidance.

Researchers are also exploring other antioxidants, anti-inflammatory medicines, growth factors, and small molecules that affect pathways involved in retinal-cell survival. Because these treatments do not necessarily depend on one gene, some may eventually apply to several forms of RP.

Cell therapies explore whether damaged retinal cells can be supported or replaced.

Some treatments use cells that release substances intended to help the remaining photoreceptors survive. Others aim to transplant new photoreceptors or retinal cells to replace those that have been lost.

Researchers also use stem cells to grow retinal organoids, small models of retinal tissue created in a laboratory. Organoids allow scientists to study how a person's genetic variant (definition: A change in a gene's DNA sequence. A variant can be harmless, or it can disrupt how the gene works and cause disease.) affects retinal cells and test possible treatments before they are used in people.

Cell transplantation is challenging because new cells must survive, connect with the existing retina, and communicate with the brain. Although cell-based treatments are being studied in people, they remain experimental.

Optogenetics (definition: An experimental approach that adds a light-sensitive protein to retinal cells that don't normally respond to light, giving them a new way to detect it.) is being studied mainly for people with advanced vision loss whose photoreceptors no longer respond effectively to light.

Instead of replacing the lost photoreceptors, optogenetic treatments introduce a light-sensitive protein into other surviving retinal cells. The goal is to allow those cells to detect light and send information through the optic nerve to the brain.

Several optogenetic treatments have entered human clinical trials. Some are used with specialized glasses or other equipment that process visual information before it reaches the treated eye. The goal is to provide useful visual information, such as the location or shape of an object, rather than recreate ordinary sight.

Retinal prostheses and related devices attempt to bypass photoreceptors that no longer work.

These systems may use a camera, implanted electrodes, light-sensitive materials, or other technology to stimulate the remaining retina or another part of the visual pathway.

The information they provide is much more limited than natural vision. Researchers are working to improve image detail, comfort, reliability, and the brain's ability to interpret the signals.

The original RP Hope website also followed several less established areas of research. These include:

• Nanobodies: Very small antibody fragments that can bind to a particular protein. Researchers have developed nanobodies that stabilize altered forms of rhodopsin (definition: A light-sensitive protein in rod photoreceptors, produced by the RHO gene, that's essential for seeing in dim light.), the protein produced by the RHO gene. This work remains at an early laboratory stage.
• N-acetylcysteine amide, or NACA: An antioxidant compound designed to enter cells more easily and reduce oxidative damage. Research related to RP has largely remained preclinical (definition: Research done in cells or animals, before a treatment is considered ready to be studied in people.).
• Exosomes: Tiny packages released by cells that carry proteins, genetic material, and other signals. Researchers are studying whether exosomes could protect retinal cells or deliver treatments, but their safety and effectiveness for RP have not been established.
• Light-activated medicines: Compounds designed to make surviving retinal cells respond to light. Like optogenetics (definition: An experimental approach that adds a light-sensitive protein to retinal cells that don't normally respond to light, giving them a new way to detect it.), these approaches may eventually offer a way to restore limited visual function without repairing the original RP gene.
• Cell reprogramming: An early research strategy that attempts to encourage cells already present in the retina to become new photoreceptors or support retinal repair.

These ideas are scientifically promising, but most remain much further from routine patient care than treatments already in clinical trials.

A possible therapy usually passes through several stages:

• Laboratory research: Scientists test the idea in cells, retinal organoids, or other laboratory models.
• Preclinical research: The treatment is studied in animals to examine its effects and possible risks.
• Phase 1 clinical trials: A small number of participants receive the treatment, with the main focus on safety and dosage.
• Phase 2 clinical trials: Researchers continue studying safety and look for evidence that the treatment may work.
• Phase 3 clinical trials: The treatment is tested in a larger group, often against a placebo (definition: An inactive treatment made to look like the real one, used in some trials so researchers can tell whether the actual treatment is responsible for any effect.), sham procedure (definition: A procedure that mimics the steps of a real treatment, such as an injection, without delivering the experimental therapy — used for comparison in some trials.), or current standard of care.
• Regulatory review: Agencies such as the FDA review the evidence and decide whether the treatment should be approved.

Many possible therapies do not make it through every stage. Clinical trials are designed to find out whether a treatment truly works and whether its benefits outweigh its risks.

A therapy or clinical trial may depend on:

• The gene involved
• The specific variant within that gene
• How the condition is inherited
• The amount and location of functioning retina that remains
• Age, general health, and previous treatments
• The eligibility requirements and location of a clinical trial

Knowing your gene does not guarantee that a treatment or trial is available. However, it can help narrow the search and connect you with research that is most relevant to your form of RP.

A treatment described in a research article or listed in a clinical trial is not necessarily proven to be safe or effective. Decisions about genetic testing, treatment, supplements, or clinical-trial participation should be discussed with a qualified eye specialist or genetic counselor.