WE ARE RACING TOWARDS A CURE
HOW H-ABC DISEASE RESEARCH HAS PROGRESSED
Although the path to a cure is a difficult one, a significant amount of progress has been made on H-ABC disease research already.
In 2002, Dr. Marjo S. van der Knaap identified H-ABC using magnetic resonance imaging (MRI), which has become a key part of detecting brain tissue patterns that are characteristic of the disease.
In 2013, Dr. Vanderver and others discovered that those affected by H-ABC carry a mutation in the TUBB4A gene. With genetic testing, doctors are now able to confirm changes in the TUBB4A gene and diagnose H-ABC.
In 2017, Dr. Ian Duncan concluded that TUBB4A related leukoencephalopathy is the human counterpart of a neurological condition in rats. This rat model could serve as a testing ground for medications that inhibit microtubule formation.
In 2017, Dr. Vanderver and others reported that different TUBB4A mutations affected oligodendrocytes and neurons to different degrees, explaining different disease presentations in different people. This study also showed in cells that microtubule function is affected by TUBB4A mutations.
In 2019, Dr. Vanderver and others published the first mouse model with a TUBB4A mutation specific to H-ABC. This mouse model will be used to explore treatments for H-ABC and TUBB4A related leukoencephalopathy.
Already, those who have made the choice to stand with us and fight have made a huge difference in the lives of those affected by H-ABC.
Perform cellular-level research of the disease—COMPLETE
Research biological makeup of the disease—COMPLETE
Determine best approach for gene therapy—IN PROGRESS
Get FDA approval for clinical trial
Start clinical trial
At this time, the team at CHOP is looking at gene therapy to treat H-ABC, as its ability to cure cellular-level diseases is promising. Once they’re able to determine the best approach for gene therapy, they can then get started on obtaining FDA approval and launching a clinical trial.
WHAT A CURE FOR H-ABC MAY LOOK LIKE
The team at CHOP is now at the interim stage of their research for a cure. Current results indicate they are on the right path toward launching a clinical trial in the near future; however, more funding is still needed.
This timeline can take up to four years if all goes as planned, but the costs are targeted at £4 million, and the funding and level of attention given to this disease dictate the timeline.
A program of work has been defined by CHOP to explore feasibility of treatment of H-ABC using three possible approaches:
1) Reduce the expected toxicity to cells from the mutated tubulin by using an approach that captures RNA before it becomes proteins (antisense oligos or ASOs).
2) Out compete the mutant tubulin through overexpression of wild type (i.e., correct) TUBB4A in the cell. Dr. Vanderver will be testing if this approach is successful in her animal and cell models in the lab.
3) Correct the mutation in the tubulin gene through a highly novel gene-editing approach that can correct spelling mistakes in genes (using CRISPR to correct the mutation at the DNA level for H-ABC). We are very happy to announce that a CRISPR expert at Harvard/MIT, Professor David Liu, will be working with the research team at CHOP. Professor Liu’s work is highly prominent in the field, having pioneered the use of engineered CRISPR Cas variants with improved specificity and targeting ability. The advantage of this approach is that it brings a truly cutting-edge technology to treat H-ABC.
2019 AAN Poster Charsar
Brittany Charsar’s poster on the natural history study of H-ABC
The latest paper from Adeline Vanderver’s lab describing the TUBB4A H-ABC mouse model, key to understanding the pathogenesis of the disease and a model for developing future therapies.
NDD Proposal Charsar
Brittany’s proposal outlining the approach and purpose for a retrospective natural history study of H-ABC caused by TUBB4A mutations