Cell-based therapies and gene-independent approaches have the potential to benefit anyone with Usher syndrome, regardless of their subtype. Examples include stem cells, retinal progenitor cells, neuroprotection, optogenetics, nutritional approaches, etc. Here, we outline the various approaches that have the potential to help anyone living with Usher syndrome.
Each research project listed below will include a graphic of the research continuum. The gold box indicates where this project falls on the continuum, illustrating its progress towards reaching people living with Usher syndrome, from "Bench to Bedside."
Safety and Efficacy of NPI-001 Tablets for RP Associated With Usher Syndrome (SLO RP)
Dr. Lee Anderson with sponsors and collaborators from Nacuity Pharmaceuticals Inc. and Foundation Fighting Blindness in Australia are looking at NPI-001 Tablets, an antioxidant drug. Their study will examine the safety and efficacy of these oral NPI-001 Tablets compared to placebo tablets for participants who have vision loss due to retinitis pigmentosa (RP) with Usher syndrome. The study takes place over the course of 24 months. This study is expected to be completed in September 2023.
Stem Cell Therapy for USH
Edwin Stone, M.D., Ph.D.:
University of Iowa
Stone and his team at the University of Iowa are working to develop a cure for Usher syndrome along with other types of retinitis pigmentosa. They are working to halt further retinal degeneration from USH1F through gene replacement and to repair damaged retinal photoreceptor cells with new cells made from the patient's own skin cells with the goal of a clinical trial once safety and efficacy are determined.
The University of Iowa Institute for Vision Research
Clinical Trial for Safety and Tolerability of hRPC in Retinitis Pigmentosa (hRPCRP)
ReNeuron, a UK-based stem cell research company, that focuses on developing stem-cell therapies that target areas of "significant unmet or poorly met medical need." They have used their stem cell technologies to develop cell-based therapies for significant diseases where cells can be readily administered to any eligible patient without the need for additional drug treatment. Currently, they are developing the human retinal progenitor cell line (hRPC) for the treatment of retinal diseases such as retinitis pigmentosa (RP).
- Positive Preliminary Data: Significant improvement in vision in first cohort of Phase II subjects in US trial of hRPC cell therapy in retinitis pigmentosa (February 20, 2019)
- ReNeuron Website
- Additional Information on hRPCs for Retinal Diseases
- Clinical Trial for the Safety and Tolerability of hRPC in Retinitis Pigmentosa (hRPCRP)
Clinical Trial for Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
jCyte was founded in 2012 by Drs. Henry Klassen and Jing Yang, who have spent decades investigating the mechanisms that drive retinitis pigmentosa (RP) and other retinal diseases. Their work led to the creation of retinal progenitor cells (RPCs), a type of stem cell that can only become retinal cells. Clinical studies have shown that these cells could rescue and even replace diseased retinal cells. Early results from a phase 1/2a study have shown the treatment is safe and does not trigger an immune response. They have completed the enrollment and recruitment for their current phase 2b trial.
- jCyte Website
- Additional Information on jCells
- ClinicalTrials.gov listing for Phase 1/2a Study
- ClinicalTrials.gov listing for Phase 2b Study
Cedars-Sinai, a non-profit healthcare organization based in Los Angeles, has received authorizations from the FDA to launch a 16-person, Phase 1/2a clinical trial of human neural progenitor cells--stem cells that have almost developed into neural cells--for patients with RP. The trial is being funded by a $10.5 million grant from the California Institute for Regenerative Medicine. The study's principal investigator is Clive Svendsen, PhD, professor of Biomedical Sciences and Medicine and director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute.
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Intravitreal injection of human retinal progenitor cells (hRPCs;jCells) is a novel stem cell treatment currently in development for retinitis pigmentosa (RP. In a recently completed phase 2b study, this treatment was injected into the jelly-like center or vitreous of the eye and has demonstrated promising biologic activity and an excellent safety profile. In this study, 84 patients diagnosed with RP and with best-corrected visual acuity (BCVA) between 20/80 to 20/800 were randomly assigned to 2 different doses (low or high) of jCells or a placebo. The primary end point (or target outcome) was the mean change in the BCVA at 12 months; the secondary end points were identification of the lowest light level at which patients could navigate through a structured mobility maze, along with the mapping of each patient’s kinetic visual field, the evaluation of their performance on contrast sensitivity testing, and completion of a low vision–specific quality-of-life questionnaire. In a post hoc analysis of this target population, an early and significant improvement in vision was seen in the higher-dose group, with average gain of 16 letters at month 12 compared with 2 letters in the control group. Improvement in the higher-dose group compared to the control group was also true for the secondary outcomes. While there were some mild cases of eye inflammation and one severe case of hypertension associated with treatment, these adverse effects were addressed. These study results showed that intravitreal injection of allogeneic jCells that were not derived directly from the patient shows promising results. The study is expected to continue with expected redosing of patients and further monitoring as this treatment is not expected to be permanent.
What this means for Usher syndrome: These results from a Phase 2b study demonstrate that intravitreal injection of retinal progenitor stem cells shows measurable improvement in vision and may be a viable treatment option in the future for both Usher and RP patients.
Researchers have discovered a technique for directly reprogramming skin cells into light-sensing rod photoreceptors used for vision. The laboratory-made rods enabled blind mice to detect light after the cells were transplanted into the animals’ eyes. According to Anand Swaroop Ph.D., senior investigator, “This is the first study to show that direct, chemical reprogramming can produce retinal-like cells, which gives us a new and faster strategy for developing therapies for age-related macular degeneration and other retinal disorders caused by the loss of photoreceptors.” The immediate benefit of this technique will be the ability to develop models to allow us to study the mechanisms of the disease and design better cell replacement approaches. Induced pluripotent stem (IPS) cells take about six months to create, however direct reprogramming takes only about ten days to convert skin cells into functional photoreceptors. A clinical trial to test the therapy in humans for degenerative rental diseases such as retinitis pigmentosa is in the works.
What this means for Usher syndrome: This new technique holds promise for treatment of many retinal degenerative diseases, including Usher syndrome.
Stem cell technology has enabled new possibilities for understanding and treating rare diseases such as Usher syndrome. The technology for stem cell treatment is still relatively new and complex. Unfortunately, several private clinics are attempting to financially capitalize on patients’ desperation and confusion for a cure. David Gamm, MD, PhD, a researcher at the University of Wisconsin-Madison, wrote an article for Foundation Fighting Blindness explaining the ten things we should know before falling victim to a retinal stem cell scam. Even if the treatment does not cause physical harm, it can result in significant financial damage; therefore, it is important to be aware of these scams.
The ReNeuron Group has announced positive long-term data from its ongoing phase 1/2a clinical trial of its hRPC (human retinal progenitor cells) stem cell therapy candidate in Retinitis Pigmentosa. In October 2019 at the American Academy of Ophthalmology Meeting in San Francisco, data presented by Pravin Dugel, MD showed “a group of subjects who had a successful surgical procedure with sustained clinically relevant improvements in visual acuity compared with baseline, as measured by the number of letters read on the ETDRS chart.” The company has submitted a protocol amendment to the FDA to expand their 1/2a study to treat up to a further nine patients in the phase 2a segment of the study with a dose of two million hRPC cells compared to the dose of one million cells used so far. The amended trial protocol allows for a greater range of pre-treatment baseline visual acuity in patients and includes changes that enhance the ability to use microperimetry testing to measure and detect changes in retinal sensitivity in patients treated. If the amendment is approved the company expects to have sufficient data to commence a pivotal clinical study with its hRPC cell therapy candidate in RP by 2021. Furthermore, this clinical program has been granted Orphan Drug Designation in Europe and the US, as well as Fast Track designation from the FDA.
What this means for Usher syndrome:That Usher patients may benefit from this stem cell therapy in the near future if the amendment is approved and the company obtain sufficient data for the initiation of the pivotal clinical trial .
The aim of this study is to determine if umbilical cord Wharton’s jelly derived mesenchymal stem cells implanted in sub-tenon space have beneficial effects on visual functions in RP patients by reactivating the degenerated photoreceptors in dormant phase. 32 RP patients participated in the study and were followed for 6 months after the Wharton’s jelly derived mesenchymal stem cell administration. Regardless of the type of genetic mutation, sub-tenon Wharton's jelly derived mesenchymal stem cell administration appears to be an effective and safe option. There are no serious adverse events or ophthalmic / systemic side effects for 6 months follow-up. Although the long-term adverse effects are still unknown, as an extraocular approach, subtenon implantation of the stem cells seems to be a reasonable way to avoid the devastating side effects of intravitreal/submacular injection.
What this means for Usher syndrome: If successful, this stem cell therapy will help Usher patients to recover their vision while minimizing the invasive adverse effects of the treatment.
Researchers at the National Eye Institute are launching a clinical trial to test the safety of a novel patient-specific stem cell-based therapy to treat geographic atrophy, the advanced “dry” form of age-related macular degeneration (AMD), a leading cause of vision loss among people age 65 and older. This is the first clinical trial in the USA to utilize replacement tissues from patient-derived induced pluripotent stem cells (iPSC). Under the phase I/IIa clinical trial protocol, 12 patients with advanced-stage geographic atrophy will receive the iPSC-derived RPE implant in one of their eyes. The patients will be closely monitored for at least one year to confirm safety.
What this means for Usher syndrome: This trial could pave the way to stem cell treatments of other eye diseases, including Usher syndrome.
Cedars-Sinai, a non-profit healthcare organization based in Los Angeles, has received authorization from the FDA to launch a 16-person, Phase 1/2a clinical trial of human neural progenitor cells—stem cells that have almost developed into neural cells—for patients with retinitis pigmentosa (RP). The trial will be launched after investigators receive the final institutional review of the study protocol. The trial is being funded by a $10.5 million grant from the California Institute for Regenerative Medicine. The initial study was conducted by Dr. Shaomei Wang, MD, PhD, a professor of Biomedical Sciences and a research scientist in the Eye Program at the Board of Governors Regenerative Medicine Institute. He showed that human neural progenitor cells have the potential to treat RP. The clinical trial will be directed by Dr. Clive Svendsen, PhD, professor of Biomedical Sciences and Medicine and director the Cedars-Sinai Board of Governors Regenerative Medicine Institute. Dr. David Lao, MD, from Retina-Vitreous Associates Medical Group in Beverly Hill, will be responsible for the subretinal injection of the cells into patients. The ultimate goal of this therapy is to restore the vision by replacing the defective photoreceptors.
What this means for Usher syndrome: This means that more potential stem-cell based treatments are becoming available to treat Usher patients. Since photoreceptors are the main cell group affected in Usher syndrome, the possibility of successfully replacing them with healthy cells give hope to patients that are losing their sight. Still we need to be careful and wait for the results of this new clinical trial.
Researchers in Germany have recently developed a “retina-on-a-chip” which combines living human cells with an artificial tissue-like system. The scientists describe their work as “merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human Retina-on-a-Chip platform.” Ophthalmologic drugs largely rely on animal models, which often do not provide results that are translatable to human patients. In this study, researchers present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell-types derived from human induced pluripotent stem cells (hiPSCs).
What this means for Usher syndrome: this model can be used to test hundreds of drugs for harmful effects on the “human” retina very quickly and enables scientists to take stem cells from a specific patient and study both the disease and potential treatment in the individual’s own cells.
To develop biological approaches to restore vision, scientists developed a method of transplanting stem cell-derived retinal tissue into the retina of an animal model, a cat. Human embryonic stem cells were successfully grafted into the retina of cats. The researchers observed strong infiltration of immune cells into the graft and surrounding tissue in the cats treated with prednisolone alone. The cats treated with prednisolone plus cyclosporine A showed better survival and low immune response to the grafts. This work demonstrates the feasibility of engrafting human embryonic stem cell-derived retinal tissue into the retina of large-eye animal models. Transplanting retinal tissue in degenerating cat retina will enable rapid development of preclinical work focused on vision restoration.
What this means for Usher syndrome: This procedure may provide a platform for testing stem cell-based therapies to treat Usher syndrome patients.
ReNeuron Group plc has announced the latest updated positive preliminary results in the company’s ongoing phase 1 and 2a clinical trial of its human retinal progenitor cell (hRPC) therapy candidate in retinitis pigmentosa. All three subjects in the first group of phase 2a have demonstrated a sustained and further improvement in vision compared to their pre-treatment baseline.
What this means for Usher syndrome: This potential therapy could provide a means to restore lost vision in Usher syndrome patients.
Stem cells are cells that have the capability of becoming any type of cells in an organism and in the right environment. Researchers are trying to use stem cell therapy to replace lost photoreceptors and preserve residual photoreceptors during retinal degeneration. One of the problems is that the degenerative microenvironment that already exists in the diseased retina compromises the fate of grafted cells. The desired donor cells will need to have both proper regenerative capability and the ability to improve their own microenvironment. For this purpose, the authors of the present work used specific cell surface molecules that help to kill tumorigenic embryonic cells and at the same time enrich retinal progenitor cells. The retinal progenitors were obtained from embryonic stem cells derived from retinal organoids (three dimensional structures derived from pluripotent cells) that were grafted into retinal degeneration rat and mouse models. After three months post-treatment, those animals showed a 40% increase in healthy photoreceptor cells and a decrease in inflammatory molecules, demonstrating the importance of a healthier environment for the grafted cells.
What this means for Usher syndrome: These two features of the organoid systems, regenerative capability and generation of a healthier microenvironment, will, very likely, benefit Usher patients as an additional therapy to delay or prevent photoreceptor loss.
ReNeuron Group, a UK-based global leader in the development of cell-based therapeutics, announced positive preliminary results in the company’s ongoing Phase 1/2 clinical trial of its human retinal progenitor cells candidate therapy for the blindness-causing disease, retinitis pigmentosa (RP). All three subjects in the first group of the Phase 2 part of the trial demonstrated a significant improvement in vision at the follow-up compared to their pre-treatment baseline and compared with their untreated control eye.
What this means for Usher syndrome: A similar cell-based therapy tailored to Usher syndrome may help restore vision.
A new purple protein, bacteriorhodopsin, has made its way from a tiny laboratory in Farmington, Connecticut, all the way up to the International Space Station. Since bacteriorhodopsin is light-sensitive, researchers hope to implant it into human eyes. The thought is that the protein could be used to replace cells that die due to diseases like retinitis pigmentosa and age-related macular degeneration. To simulate the cells, the laboratory in Farmington needs to build what it is called “organic implants” by layering the bacteriorhodopsin onto a film and dipping it over and over into a series of solutions. These solutions need to have a uniform distribution that can be adversely affected by gravity. To test this, LambdaVision has secured a spot for their experiment aboard the International Space Station, using funding from the ISS National Lab and Boeing.
What this means for Usher syndrome: These “organic implants”, composed of bacteriorhodopsin, could be capable of replacing dying photoreceptors in the retina.