Development of a Novel Treatment Strategy and Unique Methods of Delivery to the CNS for Amyotrophic Lateral Sclerosis
Abstract
Background information: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that is characterised by the loss of motor neurons. In 97% of cases, abnormal aggregates of a protein called TDP-43 are found in post- mortem tissue. ALS researchers believe that the aggregation of TDP-43 leads to motor neuron death and therefore development and progression of disease. Rationale and feasibility of the proposed research project: We have identified a second protein, p62, that is over abundant in ALS and show that increased levels of p62 causes TDP-43 to aggregate in a manner reminiscent of that seen in ALS-affected neurons. We found that a specific region of p62 is required for this aggregation to occur. We have developed gene-targeted therapeutic strategies that remove this region, and predict that this will prevent abnormal TDP-43 aggregation. Our project will further develop these gene therapies by testing them in patient-derived motor neurons and a TDP-43 mouse model of ALS. We have also identified several compounds that clear TDP-43 aggregates via activation of an intrinsic garbage removal system that is present in all cells, autophagy. Our project will test these autophagy-activating compounds in combination with our gene therapies to definitively establish that our gene therapies, either alone or in combination with these compounds, prevents and rescues the TDP-43 pathology associated with ALS. Lastly, while gene therapies are increasingly being developed for neurodegenerative disorders, delivery of these therapies to the brain and spinal cord (central nervous system, CNS) remains a significant limiting factor in the efficacy of these therapies. Thus, we will test a series of modifications to our gene therapies to identify those that significantly enhance delivery to the CNS. Applicability of the research: One of the issues with gene therapy for neurodegenerative diseases is that delivery to the brain and spinal cord is minimal due to the presence of the blood-brain-barrier, designed to protect the brain from toxins and pathogens. In this research project we have designed a suite of variations to apply to gene therapies that we envisage will enhance delivery to the CNS. These modifications can then be applied to any gene therapies developed for various neurodegenerative disorders, including ALS. Beneficiaries of the research: The main intended beneficiaries of the research are individuals with sporadic ALS, that is patients without a known family background or genetic component to their disease. Only 10% of ALS cases are familial, so our research will benefit almost all ALS patients. Our research has highlighted a genetic target that can be manipulated leading to a decrease in the TDP-43 pathology that is present in 97% of ALS cases. It is likely that this will be most beneficial to patients that are treated early following diagnosis. Unfortunately, our therapeutic strategy will not be able to reverse the damage already done as it cannot replace lost motor neurons. However, research by other investigators is underway to identify ways to replace lost motor neurons. Therefore, in future our treatment strategies could be used in conjunction with therapies that are developed to replace those motor neurons. Potential clinical applications, benefits, and risks: Currently gene therapies like ours are administered directly via injection into the spinal cord, an administration route that has significant potential risks. Our research aims to identify modifications that will allow gene therapies to be administered by injection into the bloodstream. The outcomes of our work will be applicable to existing and future gene therapies developed for neurodegenerative diseases to enhance their efficacy. Slowing the progression of ALS will extend the productive life of patients, improve their well-being, and reduce the burden on the health care system. Gene therapies can cause toxicity and this ne
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310411
Entities
People
- Sarah Rea
Organizations
- Murdoch University
- United States Army