Treatment of neurodegenerative diseases (HD/jNCL3)
The aim of this project is to screen different plant extracts and monosubstances for their ability to attenuate pathology in mouse models of the neurodegenerative diseases Huntington’s disease (HD) and Batten disease, the juvenile form of neuronal ceroid lipofuscinosis (jNCL3).
Our research will (i) help to find new drugs against the diseases, (ii) provide valuable new insights into their pathogenesis and (iii) identify novel targets and optimal time windows for treatment of patients.
The experiments will be carried out in mice. Including experimental animals, breeding animals for experiments and strain maintenance, and siblings with undesired genotypes, this application describes the use of up to 22,988 animals. Notably, we aim to find a treatment that will ameliorate the disease and thus, potentially postpone the disease onset. Therefore, long-term monitoring of animals is absolutely necessary, but may lead to at most 120 animals reaching very old age and thereby falling into the category of severe distress. The remaining animals are expected to experience mild to moderate distress.
The 3 Rs were taken into consideration during the planning of this project. The development of neurodegenerative diseases involves a complex interplay of different cell types in three-dimensional tissues. To date, there are no in vitro models that can effectively reproduce these complex settings to deliver reliable results. Thus, animal models are required to identify therapeutic targets and optimal time windows for effective treatment of neurodegenerative diseases. Moreover, before drugs can advanced to clinical studies in humans, animal models provide an inevitable mean to exclude severe side effects. While we cannot replace certain experiments, we reduce animal numbers by phasing experiments in such a way that only research paths yielding statistically significant and thus relevant results will be pursued further, hence minimizing the number of animals needed to obtain robust results. Furthermore, all methods and animal models that we plan to use in this project have been established in our research group for a while. All treatments which can cause pain or significant stress in animals will be performed under general anaesthesia. Thus, we expect the harm inflicted on the animals to be minimal.
Our research will (i) help to find new drugs against the diseases, (ii) provide valuable new insights into their pathogenesis and (iii) identify novel targets and optimal time windows for treatment of patients.
The experiments will be carried out in mice. Including experimental animals, breeding animals for experiments and strain maintenance, and siblings with undesired genotypes, this application describes the use of up to 22,988 animals. Notably, we aim to find a treatment that will ameliorate the disease and thus, potentially postpone the disease onset. Therefore, long-term monitoring of animals is absolutely necessary, but may lead to at most 120 animals reaching very old age and thereby falling into the category of severe distress. The remaining animals are expected to experience mild to moderate distress.
The 3 Rs were taken into consideration during the planning of this project. The development of neurodegenerative diseases involves a complex interplay of different cell types in three-dimensional tissues. To date, there are no in vitro models that can effectively reproduce these complex settings to deliver reliable results. Thus, animal models are required to identify therapeutic targets and optimal time windows for effective treatment of neurodegenerative diseases. Moreover, before drugs can advanced to clinical studies in humans, animal models provide an inevitable mean to exclude severe side effects. While we cannot replace certain experiments, we reduce animal numbers by phasing experiments in such a way that only research paths yielding statistically significant and thus relevant results will be pursued further, hence minimizing the number of animals needed to obtain robust results. Furthermore, all methods and animal models that we plan to use in this project have been established in our research group for a while. All treatments which can cause pain or significant stress in animals will be performed under general anaesthesia. Thus, we expect the harm inflicted on the animals to be minimal.
Etterevaluering
Fra HKs vedtak:"I klagebehandlingen vurderte vi det slik at gjentatt administrering via oral sonde (oral gavage) eller intraperitonale injeksjoner ikke er så belastende på dyrene som det førsteinstansen la til grunn i sin behandling av søknaden. Vår vurdering bygget på at det finnes mye dokumentasjon om hvilken belastning disse prosedyrene medfører hvis de utføres av kompetent personell. Vi la til grunn at personellet som skal håndtere dyrene i dette forsøket, har nødvendig kompetanse til å utføre prosedyrene på en så skånsom måte som mulig.
Vi unnlot imidlertid å klassifisere forsøket. Vi finner at forsøket skal klassifiseres som moderat belastende etter forsøksdyrforskriftens § 7, vedlegg B, jf. instruks om Mattilsynets forvaltning av forsøksdyrforskriften (forsøksdyrinstruksen) § 8, annet ledd, bokstav c og § 11. Klassifiseringen vil inngå som en del av søknadssammendraget publisert på Mattilsynets nettsider.
Evaluering
Ifølge forsøksdyrinstruksen § 13 skal alle forsøk som omfatter bruk av primater, og forsøk som er klassifisert som betydelig belastende, evalueres av Mattilsynet etter at de er fullført. Moderat belastende, lett belastende og terminale forsøk med andre dyr enn primater skal ikke evalueres rutinemessig. Selv om dette forsøket klassifiseres som moderat belastende, mener vi en evaluering vil kunne gi
nyttig informasjon som kan bedre dyrevelferden i senere lignende forsøk. Vi setter derfor som
vilkår at forsøket etterevalueres. Det betyr at du må sende inn dokumentasjon som gjør det mulig å
evaluere:
1) Om forsøkets formål ble nådd
2) Hvilke skadevirkninger dyrene ble utsatt for og
3) Faktorer som kan medvirke til at framtidige forsøk blir bedre mht. 3R.
Denne informasjon må sendes til Mattilsynet via det elektroniske søknadssystemet FOTS
senest fire måneder etter at forsøket er avsluttet.
Vi unnlot imidlertid å klassifisere forsøket. Vi finner at forsøket skal klassifiseres som moderat belastende etter forsøksdyrforskriftens § 7, vedlegg B, jf. instruks om Mattilsynets forvaltning av forsøksdyrforskriften (forsøksdyrinstruksen) § 8, annet ledd, bokstav c og § 11. Klassifiseringen vil inngå som en del av søknadssammendraget publisert på Mattilsynets nettsider.
Evaluering
Ifølge forsøksdyrinstruksen § 13 skal alle forsøk som omfatter bruk av primater, og forsøk som er klassifisert som betydelig belastende, evalueres av Mattilsynet etter at de er fullført. Moderat belastende, lett belastende og terminale forsøk med andre dyr enn primater skal ikke evalueres rutinemessig. Selv om dette forsøket klassifiseres som moderat belastende, mener vi en evaluering vil kunne gi
nyttig informasjon som kan bedre dyrevelferden i senere lignende forsøk. Vi setter derfor som
vilkår at forsøket etterevalueres. Det betyr at du må sende inn dokumentasjon som gjør det mulig å
evaluere:
1) Om forsøkets formål ble nådd
2) Hvilke skadevirkninger dyrene ble utsatt for og
3) Faktorer som kan medvirke til at framtidige forsøk blir bedre mht. 3R.
Denne informasjon må sendes til Mattilsynet via det elektroniske søknadssystemet FOTS
senest fire måneder etter at forsøket er avsluttet.
Begrunnelse for etterevalueringen
We have performed the detailed evaluation of two mouse models (HD and jNCL3) and repurposed compounds (used for other diseases than HD). We can now state which points in time could facilitate specific effects on disease initiation. Despite previous discussions in the scientific community, we can confirm that under specific conditions, an immunomodulatory or anti-inflammatory treatment with repurposed drugs are efficient and that ABC transporter deficiency of A7 has actually beneficial effects. The latter opens now for more detailed clinical studies for testing of interference.
We will continue with this HD research perspective and plan currently a phase IIb patient study with one of the tested compounds (repurposed drug) in a National Center for Motor Diseases with sufficient amount of patients.
The anticipated total number of animals planned for this application was by far not reached. The animals in the experimental treatment groups and HD background anticipated ‘moderate belastning’, all others ‘low belastning’.
The zQ175dnxABCA7ko strain shows a reduced phenotype (partially protected).
Despite the recent developments of new in vitro models for brain structure investigations (3D models), the investigation of neurodegenerative diseases relies on animal disease models to generate the pathological protein deposition and the tissue reaction as well as the gradual neuronal loss (actual clinical phenotype).
Improvements of animal handling and experimental settings must always be performed, by closely following the anticipated results, revising the setup and intensively practicing the procedures (e.g. handling, gavage).
We will continue with this HD research perspective and plan currently a phase IIb patient study with one of the tested compounds (repurposed drug) in a National Center for Motor Diseases with sufficient amount of patients.
The anticipated total number of animals planned for this application was by far not reached. The animals in the experimental treatment groups and HD background anticipated ‘moderate belastning’, all others ‘low belastning’.
The zQ175dnxABCA7ko strain shows a reduced phenotype (partially protected).
Despite the recent developments of new in vitro models for brain structure investigations (3D models), the investigation of neurodegenerative diseases relies on animal disease models to generate the pathological protein deposition and the tissue reaction as well as the gradual neuronal loss (actual clinical phenotype).
Improvements of animal handling and experimental settings must always be performed, by closely following the anticipated results, revising the setup and intensively practicing the procedures (e.g. handling, gavage).