Case Western Research receives grant from the Foundation Fighting Blindness to assess new ways to target inherited retinal diseases

Shigemi Matsuyama, DVM, PhD, associate professor of the Department of Ophthalmology and Vision Science at the Case Western Reserve University School of Medicine in Cleveland, Ohio, discusses his team’s research grant from the Foundation Fighting Blindness that is allowing them to consider a new treatment option for inherited retinal diseases (IRD).

Question:

Can you talk about the current treatment options for inherited retinal diseases and any persistent challenges or unmet needs patients face?

Shigemi Matsuyama, DVM, PhD:

Inherited retinal diseases is a group of genetic diseases resulting in vision loss. For example, retinitis pigmentosa is one IRD, and this blinding disease is known to be caused by various mutations, and more than 60 genes are listed as a host of these mutations. Theoretically, gene therapies correcting these mutations are effective to vision in these genetic diseases.

However, due to the several technical limitations, there’s only 1 FDA-approved gene therapy for retinitis pigmentosa at present, and many patients are still waiting for the development of effective treatment. Therefore, there’s a strong unmet need of the development of therapy that is effective to prevent blindness in IRD patients, the others of the causative mutations.

Question:

You and your team at Case Western received a grant from the Foundation Fighting Blindness to study a new treatment for IRD. Can you talk about the grant and the study you have planned?

Shigemi Matsuyama, DVM, PhD:

We succeeded to develop [an] orally bioactive cell death inhibitor that can penetrate the blood-retinal barrier and the blood-brain barrier. These cell death inhibitors are small compounds and rescue photoreceptors from cell death. At present, we obtained results showing that these compounds protected photoreceptor from death in 4 different mouse models of IRD. Importantly, these effects were also validated and reproduced by a third-party drug validation company.

The next important task is to convert this basic science invention to the clinically effective therapy in the FFB-funded project. We will further optimize the chemistry and administrative formulation of the cell death inhibitor, and we will select the candidate compound to move forward for FDA approval as an investigational drug. In addition to oral administration, we plan to examine whether we can develop eye drop formation to deliver our cell death inhibitor to the retina.

Question:

How do you hope this study might impact the treatment landscape for patients with IRD?

Shigemi Matsuyama, DVM, PhD:

Our cell death inhibitor is theoretically effective to IRD with different causative mutations. Therefore, it is possible that many IRD patients can use the cell death inhibitor to slow down the progression of the disease. It is important to mention that pharmacological inhibition cell death is not the method to cure the diseases, rather it is just stopping the disease process in the middle. On the other hand, gene therapies are actually the treatment to cure the disease, although it is not available for a majority of IRD patients.

However, if the retinal cells are completely dead, even the gene therapy will not work anymore because there are no cell to cure anymore. Therefore, it is important to develop technologies to prevent retinal cell death until gene therapies become available. Our cell death inhibitor may be able to provide a solution to this problem. Another part I want to mention [is] orally available drug is very patient-friendly. However, our remaining important issue is whether there is any significant toxicity if the cell death inhibitor is used for several years in humans.

At present, mouses tolerate for more than 8 months daily treatment of the cell death inhibitor, and we did not detect any significant toxicities in mice. It is possible that IRD patients may be able to prevent blindness by taking the cell death inhibitor pill every day for several years. However, mouse and human are different and there is no guarantee that the cell death inhibitor is also safe to humans. We will conduct our study very carefully to minimize the toxicities in humans by optimizing the chemistry and administration dose as well as other factors.

Question:

You and your team previously developed cytoprotective small compound-based therapeutics. Can you talk about that?

Shigemi Matsuyama, DVM, PhD:

The cytoprotective small compounds are the basis of orally available cell death inhibitors that I mentioned in the previous answers. These compounds were designed by modifying the heat compounds that rescue cells from mitochondria-dependent cell death, more specifically, Bax-induced cell death. Bax is an evolutionarily conserved protein inducing mitochondria-dependent programmed cell death in many types of degenerative diseases such as neurodegenerative diseases and ischemia reperfusion-induced tissue damage. Bax-induced cell death is known to play a major role.

My long-term goal is to develop [an] orally available Bax inhibitor that can be used to prevent cell death of essential cells in our body. In addition to the retinal diseases, our team is now testing the efficacy of the cell death inhibitors in animal models of various degenerative diseases. We are particularly interested in testing the cell death inhibitors in acute conditions such as traumatic injury associated with ischemia reperfusion cell death.

We are also interested in the use of our cell death inhibitor in the organ preservation for transplant. I hope that our cytoprotective small compounds can be used to rescue essential cells in various types of conditions in the future.

Question:

How could an oral medication that works regardless of genetic mutations potentially help patients with IRD?

Shigemi Matsuyama, DVM, PhD:

Although, there are many different genetic mutations known to induce blindness in IRD, the fundamental pathological event is the same. That is photoreceptor cell death. Bax-mediated mitochondrial-dependent cell death is known to play a role in photoreceptor deaths in mouse models of IRD. Therefore, if we can inhibit Bax, theoretically we can protect photoreceptor regardless of causative mutations. We developed [a] new Bax inhibitor screening system and developed [an] orally available Bax inhibitor that can penetrate the blood-retinal barrier through 3 years of drug screening, cell biology, biochemistry, and the medicinal chemistry efforts.

After the designing the strongest Bax inhibitor compound in cell culture system, we modified the chemical structures so that it can be used as orally available drug that can teach the retina and the brain. Actually, we designed more than 200 new chemicals to develop orally available cell death inhibitor that can protect photoreceptor in the retina. It was not easy project, but we are very lucky to succeed to develop these compounds. I’m very grateful to all the team members in this project.

Question:

Can you talk about the genetic mutation aspect of IRD? How important is genetic testing for patients with an IRD?

Shigemi Matsuyama, DVM, PhD:

Genetic testing is very important to know the cause of IRD of each patient. Even if you do not have a severe symptom, it is better to take genetic tests, especially if your family have a history of IRD. Scientists worldwide are now working very hard to develop gene therapies for each causative gene mutations, and some of them may become available in the near future. To receive the benefit of the new gene therapy, it is crucial to know the causative mutation by genetic testing. My position is that taking genetic tests is very, very beneficial and important for IRD patients.