Antisense oligonucleotide, or ASOs, are short oligonucleotides that can modify gene expression in the nervous system. ASOs can knockdown (reduce) or upregulate (increase) protein expression, depending on the functional consequence of the mutation and how to correct it.
ASOs may be particularly useful for mutations that are dominant negative which adversely affect the wild type (or healthy gene) product in the same cell as they can “knockdown” such mutations and eliminate the adverse effects. To date, the FDA has approved about ten ASO treatments for genetic disorders and there is a precedent for such treatments to go from idea to injection in under one year.
This means Henry could be treated with an ASO in the next 12-18 months, changing his life forever.
We are hopeful that an ASO is not only the most targeted and fastest treatment we could develop for Henry due to his specific mutation, but that it could later be combined with additional therapies as they are discovered. In addition, we plan to use the research we gain in developing this ASO for Henry to develop ASO’s for all those affected by AHC.
Please help us blaze this path in our race to treat our baby boy before his brain and life are impacted forever.
Treatments or Cures
There are currently no viable treatments or cures for AHC. The only medications that have been found to mask, rather than treat symptoms of AHC, are drugs like calcium channel blockers, benzodiazepines (anxiety medications), or anti-epiltpetic drugs. There is no identifiable pattern in terms of what drugs work for which patients, and often those who have epilepsy struggle with intractable seizures for the entirety of their lives.
Practically speaking, patients with AHC will continue to experience any AHC symptom at any time causing the potential for lifelong damage or death until we have a treatment.
Currently, our three foundations CureAHC, AHCF, and Hope for Annabel, are working on AAV Gene Therapy and Gene Editing projects which would offer viable treatments for our kids.
However, Henry’s mutation specifically presents a challenge as it is suspected to be dominant negative (rather than loss of function) and thus, AAV gene therapy which provides additional good copies of the needed protein would not be enough of a treatment to halt the progression of this disease. For this reason, an ASO gene therapy is necessary to target or “knockdown” the mutation that is causing dysfunction. Read more about ASOs on our ASO page.
The For Henry AHC team has been working hard in the past year since we launched to determine once and for all the underlying mechanism of Henry's mutation so we can understand if a knockdown ASO is the best treatment path for Henry. Our researchers are still working on collecting data for this, but we hope to have a definitive answer this Spring.
In addition, we have been working to gather the correct "ingredients" needed to develop an ASO. We needed something called Whole Genome Sequencing to identify targets in Henry's DNA for an ASO, and that has since been obtained. We also needed to provide samples of blood so Henry's neurons could be derived from iPSCs. That way ASOs can be tested in Henry's neurons (in vitro) to identify which ones work best. We also were able to obtain access to a mouse model carrying Henry's mutation thanks to Dr. Mikati's generous donation of the model to Jackson Labratories. This model is available for public use. We also set to work having a CRO design ASOs based on Henry's mutation and other targets specific to his DNA. We will begin testing these ASOs in Henry's neurons this spring. What's next? Once we have identified candidate ASOs based on testing them in Henry's neurons, we can move to toxcitity studies and manufacturing. Then, Henry's ASO has to go through the FDA before it can be approved for a n=1 (1 patient) use. This can be done by early 2024, but we need to cover the full cost before Henry can be injected, which leaves us with $2.5M left to fundraise.