Race to cure “the rare”: DNA level

There are many options to cure diseases with genetic background. What will be the fastest and the most efficient for a given disease is a matter of disease biology and…luck.

What are the options then? We can act on different levels:

a.       DNA

b.       RNA

c.       Protein

d.       Function

In this post I will focus on DNA level, next levels in coming posts.

If you feel lost already, it should help if you go through the post: Setting the scene: Genetics & cell biology – fundamentals

DNA is what most of you think as a first solution. After all “gene therapies” have good publicity and seem to give spectacular results.

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Bad news: Even gene therapies cannot restore all lost or underdeveloped functions. If a hand does not grow in utero, it won’t grow after a baby is born. Similarly, if you lose your hand, it won’t grow again. And unfortunately PACS2 has high expression in utero, which means, it takes part in brain development before a baby is born (PACS2 gene is important also for other organs, hence we can see in our children various symptoms related to the heart, kidneys or reproductive system; it seems however not too be that critical, as we don’t see any typical picture of PACS-patient for those organs).

Good news: Plasticity of the nervous system is high. Early intervention for children impacted by neurodevelopmental disorders can do miracles because a child brain can produce workarounds. It’s like: the fact that you don’t have a hand, does not mean you want paint because you still have other hand or legs. Obviously it is not optimal to have one hand but it does not take all the options from the table. Other practical example concerning the brain: there are more and more proofs that people living with Alzheimer disease who are bilingual have a chance to live normal live longer, even if their brain is already changed by the disease…because additional “workarounds” created by being bilingual compensate losses caused by Alzheimer [1].

Important: we don’t know yet what is impaired in utero by PACS2 mutation, hence what is lost “forever”. However we can see that many PACS2 children respond well to early therapeutic intervention what gives us hope.

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Now, coming back to drugs impacting DNA. Currently there are 2 main options under development: gene therapy and gene editing.

Gene therapy means in practice, delivering to cell nucleus the “healthy” version of a gene. To deliver gene to nucleus, inactivated viruses act as a transporter, as they have natural ability to “infect” cells. It is a great solution for diseases caused by loss of function mutations (eg. SMA), meaning that the mutation leads to too low level of produced protein. In this situation this inactivated virus delivers healthy gene, and thanks to that additional healthy copy of a gene, (more) protein can be produced.

It is not a case for PACS2 mutation. PACS2 mutation is not loss of function. There is hypothesis it may lead to gain of function or basically doing a mess in different compartments of a cell. More was said here: Small misspelling, big troubles

The other option is gene editing. But most probably there are still years until we will be able to edit genes in neural cells in patients. The first gene editing therapy was just approved in December 2023 for sickle cell disease. The way it is delivered to human body is as following: hematopoietic blood cells are taken from bone marrow of a patient (it is a place where new blood cells are normally produced). Gene editing (CRISPR/Cas9) happens ex-vivo, so outside of a patient body. Then a patient undergo high-dose chemiotherapy to remove sick cells from bone marrow, and corrected (edited) blood cells are transplanted back to a patient bone marrow. [2]

Editing genes in-vivo, so administrating something what will edit genes in patient, is one big challenge. The other is delivering this thing to neuronal cells, so overcoming blood-brain barrier.

As PACS2 Research Foundation, we are monitoring progress in this area, but we firstly focused on therapies that can be much quicker and much cheaper delivered for PACS2-patients, so exploring options for all the other "levels" :)

Sources:

[1] https://content.iospress.com/articles/journal-of-alzheimers-disease/jad230285

[2] https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease