CHM Evolving Therapies

Finding a cure for choroideremia requires careful planning and a strong understanding of how CHM varies from person to person, how the disease progresses, and what outcomes to expect. Building on this foundation, researchers are exploring multiple approaches to slow, stop, or potentially reverse vision loss.

Current strategies include gene therapy trials, DNA editing, transplantation, stem cell therapy, and other emerging techniques. Ongoing discoveries continue to give us hope, and the collaboration of scientists, clinicians, and patient communities is what drives this research forward.

The graphic below provides a summary of Evolving Therapies and the stage(s) of development they target, with darker colors highlighting specific stages. Additional information on each therapy is provided below the chart.

Source: Schneider N, Sundaresan Y, Gopalakrishnan P, Beryozkin A, Hanany M, Levanon E, Banin E, Ben-Aroya S, Sharon D. (2021). Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities. Progress in Retinal and Eye Research, 89, 101029. https://doi.org/10.1016/j.preteyeres.2021.101029

CHM Variants

Understanding a patient’s genetic testing results, including the specific type of variant that caused the CHM mutation, may help determine eligibility for future targeted therapies that are now in development. CHM can be caused by a variety of genetic variants, including nonsense, missense, frameshift, insertion, deletion, and other changes to the gene.

A total of 300 unique pathogenic CHM variants have been reported in the Leiden Open Variation Database (LOVD). Of these, 51 percent are frameshift variants, 34 percent are nonsense, 8 percent are missense, 2 percent are in-frame deletions, 1 percent are in-frame insertions, and 1 percent are in-frame indels. Other reported variants include those that result in no protein production, silent changes, and deep intronic variants. Two percent remain unknown.

Gene Specific Therapies

Genetic diseases, like choroideremia (CHM), are caused by changes in the DNA, also called mutations. In CHM, these mutations prevent the body from producing a protein called REP-1, which is essential for the survival of certain retinal cells. Without REP-1, photoreceptors and retinal pigment epithelium (RPE) cells gradually weaken and die, leading to progressive vision loss.

Gene therapy is a type of treatment that delivers a healthy copy of a gene to affected cells, allowing them to produce the missing protein and restore normal cellular function. This therapy is delivered using a vector, which is a specially engineered cell or particle that transports the gene to the target cells.

1. Natural Virus Vectors

Scientists first turned to naturally occurring viruses, such as adeno-associated viruses (AAVs), as delivery vehicles for gene therapy. These viruses are modified so they cannot cause disease but can still enter target cells. Modified AAV vectors carry a healthy copy of a gene and deliver it to affected cells to restore their function.

The first FDA-approved gene therapy for an inherited retinal disease, Luxturna for retinitis pigmentosa, uses a modified AAV2 vector. Early CHM gene therapy trials coordinated by Nightstar/Biogen and Spark Therapeutics also used an AAV2 vector carrying the CHM gene. In these trials, the vector is delivered through a subretinal injection at the back of the eye, targeting the affected area. The therapy reaches cells only near the injection site. These trials continue to collect long-term data on safety and effectiveness.

2. Next Generation AAV Vectors

There are a limited number of naturally occurring AAV vectors, and each has specific strengths and limitations. Researchers are designing improved vectors through techniques such as directed evolution or therapeutic vector evolution.

The CRF has partnered with 4D Therapeutics to develop a novel CHM gene therapy vector. This vector is designed for delivery through an intravitreal injection in the front of the eye, potentially allowing it to reach more retinal cells. This trial is in the early stages.

3. Non-Viral Vectors

Researchers are also developing non-viral vectors, including naked DNA, particle-based, and chemical-based approaches. These vectors may reduce the risk of immune reactions compared with viral vectors. The main challenge is improving delivery efficiency, which is critical for effective therapy.

Alternative Delivery Methods

In addition to subretinal and intravitreal injections, a new method is being explored: injection into the suprachoroidal space (SCS). This is the space between the sclera and choroid that wraps around the back of the eye. SCS delivery may allow a more targeted approach, achieving concentrations in the retina and choroid up to 10 times higher than with traditional intravitreal injections.

DNA Editing

DNA, or deoxyribonucleic acid, is the hereditary material in humans and nearly all other organisms. Almost every cell in the body contains the same DNA. Genome editing, also called gene editing, refers to a group of technologies that allow scientists to change DNA. These tools can add, remove, or alter genetic material at specific locations in the genome.

One of the most well-known genome editing methods is CRISPR-Cas9, which stands for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. CRISPR-Cas9 has generated excitement because it is faster, cheaper, more precise, and more efficient than previous gene editing techniques.

CRISPR-Cas9 was adapted from a natural system in bacteria. In nature, bacteria capture DNA fragments from viruses and store them in DNA segments called CRISPR arrays. These arrays help the bacteria “remember” the viruses. If the virus attacks again, the bacteria produce RNA from the CRISPR arrays to recognize the viral DNA, then use the Cas9 enzyme to cut and disable the virus.

In the lab, scientists use CRISPR-Cas9 in a similar way. They create a short piece of RNA, called a guide RNA, that binds to a specific DNA sequence. The RNA also binds to the Cas9 enzyme, which cuts the DNA at the targeted location. Once the DNA is cut, the cell’s natural repair machinery can be used to add or remove genetic material or replace a DNA segment with a customized sequence. Other enzymes besides Cas9 can also be used for genome editing.

Genome editing is of great interest for understanding, preventing, and potentially treating human diseases. Most current research uses cells or animal models to study disease. Scientists are still determining whether genome editing is safe and effective for use in people. Researchers are exploring this approach for a wide range of conditions, including single-gene disorders such as cystic fibrosis, hemophilia, and sickle cell disease.

RNA Therapies

RNA, or ribonucleic acid, is an essential molecule found in all living cells. It plays a key role in making proteins, which are the building blocks and functional machinery of the cell. RNA is produced from DNA in a process called transcription, and it carries the instructions needed to create proteins in a process called translation.

RNA therapies are designed to correct mistakes, or mutations, in RNA caused by genetic diseases. By fixing these errors, the cell can produce the protein it needs, addressing the root cause of the disease. RNA therapies can perform similar functions to traditional medicines but can also target conditions caused by missing or broken proteins. Research has shown promising results, and some RNA therapies are already helping patients worldwide.

Unlike gene therapy or CRISPR approaches, which make permanent changes to DNA, RNA therapies work at the RNA level. This means the changes are reversible, reducing the risk of permanent side effects. RNA therapies are also smaller than gene therapies, which can make them easier to manufacture and deliver. For retinal diseases, RNA therapies are often delivered directly into the eye through an intravitreal injection, allowing them to reach the affected cells efficiently.

One specific type of RNA, called transfer RNA (tRNA), helps cells build proteins from amino acids. Each tRNA reads a set of three nucleotides in messenger RNA (mRNA) called a codon. Each codon provides instructions for adding a specific amino acid to a protein. The tRNA then transfers the corresponding amino acid to the ribosome, the cell’s protein-making machinery. This process repeats along the mRNA strand until a stop codon signals the end of protein synthesis.

Transitional Read-Through Therapies

Translational read-through therapies are a pharmaceutical approach designed to address premature stop codon mutations, also called nonsense mutations, in RNA. These mutations cause the cell to stop making a protein too early, resulting in a shortened, non-functional protein.

A simple analogy is to imagine a train traveling to its destination with multiple stops along the way. A premature stop codon is like the train returning to the starting station before completing its route, leaving all the “passengers” — in this case, proteins — stranded and unable to reach their proper place in the cell.

Translational read-through therapies use specially designed compounds to help the cell bypass the premature stop signal, allowing the “train” to reach its destination and produce a functional protein. This approach does not alter a patient’s DNA or RNA permanently.

It is estimated that 30 to 40 percent of choroideremia patients may have a nonsense mutation. While read-through therapies have shown effectiveness in some cases, clinical use remains challenging and carries potential risks. Research is ongoing to determine the safest and most effective ways to use these compounds.

Stem Cell Based Therapies

Stem cells, also called progenitor cells, have the ability to develop into almost any type of cell in the body. While early stem cell research relied on cells from embryos, new technologies allow scientists to create stem cells from a patient’s own blood or skin sample. These cells are called induced pluripotent stem cells (iPSCs). iPSCs can be guided to become specific cell types, including the photoreceptors and retinal pigment epithelium (RPE) cells that are lost in choroideremia.

iPSCs are now being used to create CHM retina organoids, which are miniaturized retina structures. These organoids help researchers study CHM at the cellular level and test potential therapies. Scientists are also working to turn iPSC-derived photoreceptors and RPE cells into transplant patches that could be surgically implanted to replace areas of vision loss.

There are two main approaches to creating these transplant patches:

1. Allogenic (Donor) iPSCs

These stem cells come from healthy donors and can be produced in large quantities. They can be assembled on a scaffold with RPE cells on one side and photoreceptors on the other, forming a patch that can be implanted into the eye. The main advantages are that this approach is not disease-specific and could benefit many patients with vision loss, and it is more cost-effective. A potential challenge is the risk of the patient’s body rejecting the transplant.

2. Patient-Derived iPSCs

These stem cells come from the patient’s own cells. The iPSCs must first be genetically edited to correct the CHM mutation before they are developed into a transplant patch. The main advantage of this approach is a lower risk of transplant rejection. The challenges include a longer, labor-intensive process and higher cost.

Prostheses and Optogenetics

In advanced CHM and other inherited retinal diseases (IRDs), the photoreceptor cells that detect light and send visual signals to the brain are lost. The remaining neurons that normally carry those signals can still function. Optogenetics and prosthetic devices aim to create new signals that these neurons can deliver to the brain, allowing the brain to interpret them as vision.

Prosthetic devices include man-made implants, such as microchips, that can be placed in the eye. These chips capture light and convert it into electronic signals, which are then transmitted through electrodes to the remaining neurons in the retina. Over time, the brain may learn to interpret these signals as functional vision. Challenges include limits on the amount of signal that can be sent due to heat generated by the chip. In early studies, patients with retinal prosthetics have regained light perception and the ability to distinguish certain objects.

Optogenetics works by making retinal neurons responsive to light. Scientists use gene therapy vectors to deliver light-sensitive proteins, such as rhodopsin, to these neurons. Special wearable glasses or goggles with video cameras capture images and convert them into a coded pattern of light. This light stimulates the treated neurons, which then send signals to the brain.

Vision is naturally transmitted to the brain as a coded signal, and some research teams have created custom codes for the neurons to follow. Other trials aim to use codes closer to the brain’s natural system, which may make it easier for patients to adapt. Researchers believe that optogenetics has the potential to restore vision for people with CHM and other advanced IRDs.

Still other research is underway to improve assistive devices such as mobile apps to read currency or provide 1:1 personal assistance; smart wearable technology to help with object identification and mobility orientation; and electronic travel aids such as intelligent canes to improve safety and navigation that will help people with vision loss improve their activities of daily living.CRF is dedicated to supporting and encouraging research for all these potential therapies to address the entire spectrum of vision loss experienced by CHM patients.

Other Evolving Research

Until such time that a cure or treatment for CHM is found, there are many other areas of research underway attempting to delay the progression of vision loss by improving the overall health of the eye. These include but are not limited to:

• Reducing mitochondrial dysfunction.
• Reducing oxidative stress.
• Providing electrical stimulation to the eye to prolong visual field and acuity.
• Improving phagocytosis. Phagocytosis is a cellular process for ingesting and eliminating excess particles or debris, such as dead cells. Phagocytosis is an essential process for tissue homeostasis, or creating a healthy equilibrium in the eye.
• Utilizing nutritional supplements, a healthy diet and exercise to optimize eye functioning (see Patient Toolkit)
• Research funded in part by CRF has shown that drugs that improve melanin production represent a potential novel therapeutic avenue for CHM.

Still other research is underway to improve assistive devices such as mobile apps to read currency or provide 1:1 personal assistance; smart wearable technology to help with object identification and mobility orientation; and electronic travel aids such as intelligent canes to improve safety and navigation that will help people with vision loss improve their activities of daily living.

CRF is dedicated to supporting and encouraging research for all these potential therapies to address the entire spectrum of vision loss experienced by CHM patients