A single intravenous injection delivering two genes nearly tripled survival in cats with Sandhoff disease
A single intravenous injection delivering two genes nearly tripled survival in cats with Sandhoff disease
On September 9, Science Translational Medicine published a paper on an experiment in a feline model of Sandhoff disease. Before symptoms appeared, kittens received a single intravenous injection of AAV9, a viral vector carrying two genes needed for the enzyme HexA to function. In the high-dose group, mean survival increased from 4.3 to 12.4 months.
In Sandhoff disease, cells lack sufficient β-hexosaminidase, or Hex. As a result, a fatty substance called GM2 accumulates in lysosomes, the compartments within cells that break down substances, and damages the nervous system. To assemble HexA, the form of the enzyme that breaks down GM2, a cell needs both sets of genetic instructions: HEXA and HEXB.
Previous experiments in this feline model used two separate AAV vectors injected directly into the brain. When delivered intravenously, the vectors can enter different cells, although both sets of instructions must reach the same cell for it to assemble HexA. The authors packaged both genes into a single AAV9 vector and tested whether one injection could deliver them to the brain, spinal cord, and internal organs.
The full study text describes 15 treated kittens that received an injection at approximately one month of age. Mean survival was 4.3 months in untreated animals, 8.3 months in kittens given the low dose, and 12.4 months in those given the high dose; one cat lived to 16 months. In the untreated group, whole-body tremors began at an average age of 2.4 months. No such tremors occurred in the high-dose group, while three of the four kittens in the low-dose group developed them at a later age.
At 16 weeks after the high-dose injection, MRI showed partial preservation of brain structure. Levels of enzymes released during cell damage also decreased in the cerebrospinal fluid, the fluid surrounding the brain and spinal cord. HexA activity reached approximately 70% of normal in the hindbrain and 120% in the spinal cord.
The effects of a single intravenous injection varied across tissues. The liver had the most vector copies, but HexA activity there did not exceed 9% of normal. At later time points, brain structure and signs of inflammation in nervous tissue in some treated animals again approached the patterns seen in the untreated group.