Periodic Reporting for period 3 - iHEAR (Gene therapy of inherited and acquired hearing loss)
Okres sprawozdawczy: 2022-05-01 do 2023-10-31
According to WHO, approximately 430 million people worldwide suffer from disabling hearing loss, with sensorineural hearing loss (SNHL) being the most reported form (>90%). SNHL is associated with a pathological change in structures within the inner ear, and it can be inherited or acquired. Currently, more than 100 genes that have a role in inherited hearing loss have been identified. In addition, several factors can contribute to the development of acquired hearing loss, including the use of certain medications. Ototoxic drugs known to cause permanent damage include, for example, platinum-based chemotherapeutic agents like cisplatin. Cisplatin can be actively taken up into hair cells (HC) and spiral ganglion neurons (SGN) by various proteins on the surface of cells that act as transporters to bring substances into or out of cells. As a consequence, the presence of the ototoxic drug triggers a series of events in the affected cell types.
As the number of people projected to suffer from hearing loss is projected to be almost 2.5 billion by 2050, hearing loss is clearly an important disease that needs to be addressed. Hearing loss can affect all aspects of a person´s life, from learning difficulties in school, impediments to social interactions and problems in the work force. Although there are some medical interventions, such as hearing aids and cochlear implants, these devices do not provide the complete range of normal hearing and not all patients can be treated with these devices.
Therefore, the overall objective of this project is to develop new treatment approaches to improve hearing in hearing loss patients and to prevent hearing loss due to certain medications. To achieve these objectives, we aim to (1) replace defective / non-functional genes with intact functioning genes as a gene therapy approach to treat hearing loss, (2) protect inner ear cells from factors that may damage them and cause them to become non-functional, and (3) use induced pluripotent stem cells to model hearing loss diseases. These main objectives will help us to learn more about the biology of otic cell development and how we can use gene therapy technologies to modify inner ear cells to improve and protect hearing in patients.
As the number of people projected to suffer from hearing loss is projected to be almost 2.5 billion by 2050, hearing loss is clearly an important disease that needs to be addressed. Hearing loss can affect all aspects of a person´s life, from learning difficulties in school, impediments to social interactions and problems in the work force. Although there are some medical interventions, such as hearing aids and cochlear implants, these devices do not provide the complete range of normal hearing and not all patients can be treated with these devices.
Therefore, the overall objective of this project is to develop new treatment approaches to improve hearing in hearing loss patients and to prevent hearing loss due to certain medications. To achieve these objectives, we aim to (1) replace defective / non-functional genes with intact functioning genes as a gene therapy approach to treat hearing loss, (2) protect inner ear cells from factors that may damage them and cause them to become non-functional, and (3) use induced pluripotent stem cells to model hearing loss diseases. These main objectives will help us to learn more about the biology of otic cell development and how we can use gene therapy technologies to modify inner ear cells to improve and protect hearing in patients.
Lentiviral vectors are one tool that can be used to modify cells in gene therapy approaches. As mentioned above, over one hundred genes are known to play a role in hearing loss and for almost all of these genes, we have generated lentiviral vectors capable of delivering an intact functional copy of the gene to target cells. Also, we actively work on AAV-mediated delivery strategies. Several modifications have been tested to identify the most efficient way to produce lentiviral vectors that can deliver their therapeutic gene cargo in an optimal manner, including extent of target cell modification, expression and functionality of the therapeutic gene.
Many patients who are treated for diseases such as cancer suffer from hearing loss as a result of the therapy needed to eliminate their cancer. Therefore, we have designed novel and adapted published protocols for genome editing to allow generation of inner ear cells that are resistant to anti-cancer therapy with the hope to protect the ability of these patients to hear. Our initial in vitro results are promising, but need to be verified in vivo. Here, it will also be important to test for safety as well as feasibility.
Induced pluripotent stem cells (iPSC) are a renewable cell source that can be used to generate all different types of cells that make up an organism, e.g. a human. The great ability of iPSC to proliferate coupled with their capacity to differentiate into all different cell types, makes these cells a valuable tool for research as well as potential clinical applications. We have thus far used iPSC to study the transcription factors necessary for development of otic cells, such as inner ear hair cells and spiral ganglion neurons, which are crucial for hearing.
Many patients who are treated for diseases such as cancer suffer from hearing loss as a result of the therapy needed to eliminate their cancer. Therefore, we have designed novel and adapted published protocols for genome editing to allow generation of inner ear cells that are resistant to anti-cancer therapy with the hope to protect the ability of these patients to hear. Our initial in vitro results are promising, but need to be verified in vivo. Here, it will also be important to test for safety as well as feasibility.
Induced pluripotent stem cells (iPSC) are a renewable cell source that can be used to generate all different types of cells that make up an organism, e.g. a human. The great ability of iPSC to proliferate coupled with their capacity to differentiate into all different cell types, makes these cells a valuable tool for research as well as potential clinical applications. We have thus far used iPSC to study the transcription factors necessary for development of otic cells, such as inner ear hair cells and spiral ganglion neurons, which are crucial for hearing.
The results we have already achieved for in vivo gene transfer are beyond state of the art in the hearing field, as such successful modification of inner ear cell types has not been previously shown with lentiviral vectors. We expect the results that we will generate in this project will lead to clinical trials to improve hearing in patients. Some genes that play a role in hearing loss are too large to be delivered by other approaches, so the lentiviral vector system that we have developed, which can even deliver these very large genes, offers the possibility to correct a broader range of defective genes known to have roles in hearing loss.