Development of a Non-Human Primate Model for the Identification and Development of Novel Therapeutics for Dystonia
Abstract
Topic Area: The project will develop a non-human primate (NHP) model of dystonia; dystonia is a Topic Area covered by FY21 PRMRP. The proposed work directly addresses the Area of Encouragement Identification and development of novel research tools (cellular models, phenotypic models, etc.) to aid dystonia research. Furthermore, the model that we are proposing to develop can also be used to unravel the effect of knockdown of a gene known to be implicated in the development of dystonia on relevant circuit networks. Thus, the project will also address a second Area of Encouragement, Research to identify the relationship between specific molecular/genetic changes and circuitry/network alterations in dystonia. Rationale: The development of new drugs is a long and challenging process. Ultimately, all new drugs are evaluated in clinical trials that are designed to answer whether or not the potential drug is beneficial in treating the specific disease under study. While there is no single development path to the approval of a drug, in general, the clinical trials that are required to prove that a drug is beneficial in a neurological disorder, such as dystonia, can take years to complete and cost hundreds of millions of dollars. Therefore, the failure of a drug to demonstrate efficacy in these trials is not only devastating to the people with the disorder, but also consumes research and development resources. It is therefore imperative that only the best drug candidates are progressed into clinical trials. However, in order for this to happen, there needs to be a robust preclinical development pipeline that is able to identify weaker drug candidates and thus prevent them from entering clinical trials. One of the problems in developing a drug to treat dystonia is that the preclinical models used to evaluate potential therapeutics is not yet well enough developed to select compounds that are likely to be of clinical benefit. Thus, once a potential therapeutic has been identified, the majority of the preclinical testing in animals is performed in rodents that have been manipulated so that they have genetic deficits that are analogous to genetic mutations known to cause dystonia in humans. While these models have undoubtedly helped improve the selection of potential therapeutic clinical candidates, they are limited by several factors: • The rodent models do not completely recapitulate the pathophysiology of the disease. • There are substantial differences between the brains of humans and rodents. • Endpoints used in rodent studies are not directly translatable into clinical studies. If these limitations could be overcome, then it would be possible to select better drug candidates to enter into clinical trials that would benefit people with dystonia as well as ensuring that valuable resources are not wasted on drug candidates that, with a better preclinical development pathway, would not have entered into clinical trials. To overcome the limitations listed above, we intend to develop an NHP model of dystonia. Two major advantages of using NHPs over rodents are firstly that the brain structures and circuits are much more closely related between NHPs and humans compared to rodents and humans. As dystonia is driven by abnormal brain circuit functioning, it is very important that an animal model of dystonia contains brain circuitry that closely resembles the circuitry of humans, otherwise drugs that normalize the circuitry in rodents may have differing effects in NHPs and humans. Secondly, the behavioral repertoire of NHPs is much richer than that of rodents. This means that the behavioral symptoms that NHPs can develop much more closely resemble the human condition compared to rodents. In turn, this allows much more clinically relevant endpoints to be incorporated into the preclinical study design; for instance, primates have been used to study focal dystonia of the hands, a dystonia not easily replicated in rodents. Incor
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211043
Entities
People
- Jonathan Brotchie
Organizations
- Atuka (Canada)
- United States Army