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Life Sciences => Physiology & Medicine => Topic started by: scientizscht on 07/07/2019 22:32:47

Title: How is Zolgensma delivered in motor neurones only?
Post by: scientizscht on 07/07/2019 22:32:47
How is Zolgensma delivered in motor neurones only?

They put them in viral capsids, but how they make sure they deliver it selectively to the specific neurones?

Also how is it not degraded with time and one shot lasts a lifetime?

Thanks!
Title: Re: How is Zolgensma delivered in motor neurones only?
Post by: evan_au on 08/07/2019 12:17:06
The SMN1 gene is deficient in all cells of the body. But this genetic disease primarily impacts motor neurones.

Restoring the function of the SMN1 gene should protect motor neurones.

See: https://en.wikipedia.org/wiki/Onasemnogene_abeparvovec

$2 million for a single dose is rather steep!
- But with no alternatives available, there will be some people (and/or governments and insurance companies) willing and able to pay the price.
Title: Re: How is Zolgensma delivered in motor neurones only?
Post by: scientizscht on 09/07/2019 00:03:26
Thanks but anything on my questions?
Title: Re: How is Zolgensma delivered in motor neurones only?
Post by: evan_au on 09/07/2019 11:27:55
From a quick skim:
Quote from: OP
How is Zolgensma delivered in motor neurones only?
In theory you could modify the carrier virus so that it would target some protein found only on the surface of motor neurones.

However, I see no mention that this specific targeting has been done, so I suspect that the virus will target almost any nerve cell it runs into (and maybe other kinds of cells, too).

When it is administered into a vein, the virus could reach any cell in the body, and potentially insert the SMN gene into these cells, as well as the spinal cord.

If you can't control where it goes, you might control where it is expressed, by selecting the promoter regions to be sensitive to other RNA signals in the cell. But I haven't seen indications of this, either.

Maybe they expect that other cell types (that don't normally express SMN1) won't be damaged by the presence of this "foreign" protein?

Quote
They put them in viral capsids, but how they make sure they deliver it selectively to the specific neurones?
The AAV9 strain of the Adeno-Associated Virus does appear to have some ability to cross the Blood-Brain Barrier that keeps out many viruses.

When it is administered directly into the spinal fluid, that will target nerve cells more directly, but will probably also inject its payload into sensory nerves and the surrounding membranes too.
See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835088/

Quote
Also how is it not degraded with time and one shot lasts a lifetime?
It is double-stranded DNA, which is more stable than single-stranded DNA.
- Single-stranded DNA triggers some anti-virus immune responses that chop up DNA
- If double-stranded DNA is damaged, the body has various DNA repair mechanisms that should also repair the therapeutic DNA

There are various studies underway now to see if/when it degrades.
Title: Re: How is Zolgensma delivered in motor neurones only?
Post by: scientizscht on 09/07/2019 12:24:56
So the DNA piece is not embedded into the host genome?

It floats free in the cell and gets translated?
Title: Re: How is Zolgensma delivered in motor neurones only?
Post by: evan_au on 09/07/2019 23:40:46
Quote
It floats free in the cell and gets translated?
I suspect that it would float free in the nucleus and gets translated.
- The mechanism to translate nuclear DNA into RNA exists only in the nucleus.
- The cytoplasm outside the nucleus only has mechanisms to translate RNA into protein.

If you try to incorporate new DNA into the existing chromosomes with current techniques, it is likely that you will break some other random gene, perhaps leading to cancer.

Quote
How is Zolgensma delivered in motor neurones only?
You seem to think that this is a targeted therapy.

I get the impression that this is a first-generation non-targeted therapy - like a shotgun, it hits as many things as it can, in the hope that some of them are the intended target.
- Future, more sophisticated versions may selectively target motor neurones
- This was awarded "breakthrough" status because it is a lethal disease with no current treatment; in traditional societies, it would prove lethal by 2 years of age.
- Non-targeted therapies are "normal" in medicine. When you get an injection into a vein, or take a pill, the medication diffuses through your whole body, with the expectation that a small fraction of the medicine will actually reach the part of the body which is affected by the disease.
- The medicine which hits unplanned targets can cause unplanned effects; we call these "side-effects", and they can be severe
- But faced a 100% lethal disease by age 2, the side-effects are unlikely to be worse than the disease
- After testing on Type 1, they will move to testing on the less-severe Type 2, which is usually lethal by age 25. In this case, side-effects may cause a significant impact on quality of life.

Note: The use of AAV9 is not really a way to target the right cells; it is more a way of bypassing the blood-brain barrier that would normally prevent it from reaching the target cells.