Antisense oligonucleotide treatment
The treatment works like this: The researchers developed a noninfectious virus that carries an antisense oligonucleotide sequence designed to specifically bind the RNA coding for PTB, thus degrading it, preventing it from being translated into a functional protein and stimulating neuron development.
Antisense oligonucleotides are a proven approach for neurodegenerative and neuromuscular diseases which forms the basis for an FDA-approved therapy for spinal muscular atrophy and several other therapies currently in clinical trials.
The researchers administered the PTB antisense oligonucleotide treatment directly to the mouse’s midbrain, which is responsible for regulating motor control and reward behaviors, and the part of the brain that typically loses dopamine-producing neurons in Parkinson’s disease. A control group of mice received mock treatment with an empty virus or an irrelevant antisense sequence.
In the treated mice, a small subset of astrocytes converted to neurons, increasing the number of neurons by approximately 30%. Dopamine levels were restored to a level comparable to that in normal mice. What’s more, the neurons grew and sent their processes into other parts of the brain. There was no change in the control mice.
By two different measures of limb movement and response, the treated mice returned to normal within three months after a single treatment and remained completely free from symptoms of Parkinson’s disease for the rest of their lives. In contrast, the control mice showed no improvement.
“I was stunned at what I saw,” said study co-author William Mobley, MD, PhD, professor of neurosciences at UC San Diego School of Medicine. “This whole new strategy for treating neurodegeneration gives hope that it may be possible to help even those with advanced disease.”
What is it about PTB that makes this work? “This protein is present in a lot of cells,” Fu said. “But as neurons begin to develop from their precursors, it naturally disappears. What we’ve found is that forcing PTB to go away is the only signal a cell needs to turn on the genes needed to produce a neuron.”
Of course, mice aren’t people, he cautioned. The model the team used doesn’t perfectly recapitulate all essential features of Parkinson’s disease. But the study provides a proof of concept, Fu said.
Next, the team plans to optimize their methods and test the approach in mouse models that mimic Parkinson’s disease through genetic changes. They have also patented the PTB antisense oligonucleotide treatment in order to move forward toward testing in humans.
“It’s my dream to see this through to clinical trials, to test this approach as a treatment for Parkinson’s disease, but also many other diseases where neurons are lost, such as Alzheimer’s and Huntington’s diseases and stroke,” Fu said. “And dreaming even bigger—what if we could target PTB to correct defects in other parts of the brain, to treat things like inherited brain defects?” Fu asserted that he intends “to spend the rest of my career answering these questions.”
Sources: Google scholar: GENtech, Reddit