15 February 2021
DUKE RESEARCHERS ACHIEVE FAVORABLE RESPONSE TO GENE THERAPY IN ALTERNATING HEMIPLEGIA OF CHILDHOOD (AHC) MOUSE MODEL
In this study the Duke research group of the Mikati Lab used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene to add a normal copy of the ATP1A3 gene to the brain of AHC mice by injecting that vector into the cisterna magna (space within the skull just outside the base of the brain that has cerebrospinal fluid) and into the two lateral cerebral ventricles (spaces within the brain substance that are filled with cerebrospinal fluid).
The injections were performed in mice carrying the D801N mutation (Mahlool AHC mice). One group of these mice received the above active vector and another received a control vector without ATP1A3. Also control normal mice were injected.
Mice received the injections at age 10 days (P10) which corresponds to early infancy in human terms, the age at which AHC is usually diagnosed. The mice were then tested at age 40 days (P40, early adulthood) and 70 days (P70, mid adulthood).
The findings were the following:
- Treatment increased ATP1A3 expression and function: There was strong expression of the injected gene in brain areas close to the injection sites (see Figure 1) with increase in the enzyme activity of the ATP1A3 ATPase.
- Treatment improved survival: It is already known that without treatment about half of the D801N mice die by around the age of 70 days. In this study, all the D801N mice treated with the active vector survived during the study period. On the other hand, as expected, half of the D801N mice who did not receive the active vector died.
- Treatment improved neurological function: At P40 there was reduction of inducible hemiplegia spells, and a significant improvement in balance of the mice who received the active vector.
- Improvement in neurological function was only partial: At age 70 days only a minimal effect on balance persisted and an effect on hemiplegia spells was not observed. Also, not all neurological function improved at either age (including inducible dystonia, strength and memory at either age 40 days or 70 days which did not differ between the treated group and the control mice).
Figure 1: Green Stain shows expression of ATP1A3. The illustration shows strong expression in an area close to the active vector injections site.
This study demonstrates that, as a proof of concept, gene therapy can induce favorable effects in mice carrying the most common mutation causing AHC in humans. This encourages future research to improve the vector to allow more expression of ATP1A3 in all the brain (not just in areas close to the injection sites) for longer periods of time to get even more effects allowing translation to human trials.
by Prof. Mohamad Mikati (Duke University, Durham NC, USA)
read the report in pdf
Reference: Hunanyan AS, Kantor B, Puranam RS, Elliott C, McCall A, Dhindsa J, Pagadala P, Wallace K, Poe J, Gunduz T, Asokan A, Koeberl DD, ElMallah MK, Mikati MA.Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood. Hum Gene Ther. 2021 Feb 12. doi: 10.1089/hum.2020.191. Epub ahead of print. PMID: 33577387. link