The new gene (I don't think they are editing a gene, just inserting one) expresses the enzyme in the cells that were edited. These cells can lower the serum levels of sulphatides thereby reducing the levels else where in the body reducing the damage done by them and hopefully effectively curing the disease. It remains to be seen if it prevents lifelong impact from MLD.

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I work adjacent to this field (gene therapy), so while I do not have direct experience with MLD (the disease) nor the development of Libmeldy (the drug), I am able to peruse the data pretty well.

First, it seems clear that the cause is MLD is well-known: the deficiency of the enzyme arylsulfatase A (ARSA), which results in activity in leukocytes less than 10% of normal function. With this level of function, sulfatides build up in various tissues, eventually resulting in the destruction of the myelin sheath that is essential for nerve function. MLD is autosomal recessive, with ARSA located on chromosome 22.

So, a direct answer to your question is that since leukocytes are the cell types where the deficiency of this enzyme results in the disease state, the gene therapy which results in a new, functional version of ARSA in the stem cells which will differentiate into said leukocytes will restore efficiency of this enzyme to levels that alleviate the disease state. It would appear that restoring functionality in this specific cell type (CD34+ stem cells) is sufficient.

Some interesting notes:

The girl treated was very young, which seems to be crucial in rescuing function. Her older sister also has MLD, but her disease had progressed too far to be a candidate for the drug. Super sad and super unlucky: the parents had only a 1-in-16 chance that both of their children would have the disorder, as the parents were both carriers.

Obviously, long-term effects of this treatment are not known, as it has only recently been approved. But, researchers expect that the treatment should be lifelong because the lentivirus vector integrates into the CD34+ cells and should persist as long as that population of cells remains in the bone marrow.

The price for this drug (and other life-long gene therapy treatments) is incredibly high (in this case, I've seen 2.8 million pounds sterling quoted). This poses a number of challenges from a reimbursement standpoint, and frankly the field does not know what the best way forward is going to be. The interaction between companies, regulators, insurance, patients, etc. are all quite nuanced and the specifics differ between each of these therapies. Putting aside any ethical considerations for drugs priced this high, the actual financial logistics will always be an issue.

Hope that helped. Cheers!

Oh yes thanks! I seem to have missed the bit about leukocytes being affected.

It is quite interesting that although the brain is an immune privileged site, that any resident immune cells must come from the bone marrow lymphoid lineage and presumably it is those which are tasked with clearing up the sulfatides. The black box has been resolved :)

The gene edit is not passed on to the neurons. After a bone marrow transplant, the hematopoietic stem cells can develop in different type of blood cells. Some of these can migrate into the brain, where they can either provide the missing enzyme to the neural cells, or clean up a build up of toxic compounds in the environment of the cells. In the case of MLD, it is probably this removal of toxic compounds that is beneficial.

The bone marrow transplant part is not what is new about this approval. Bone marrow transplants have been used for brain disease like MLD for a while, however a bone marrow transplant from a donor comes with a significant risk of serious complications due to rejection of the tissue. The hope is that gene editing of a patients own bone marrow cells will be much safer. In addition they can sometimes make sure that the edited gene has a higher expression, which may boost the efficacy of the transplantation.

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The article I read recently explained that the NHS had agreed a different (undisclosed) amount of money for the treatment, and also explained that they balanced the cost of the drug against the cost of treating a person who then would develop the disease, and, of course, the emotional impact of a child's death. I suspect that care costs must be particularly high for this kind of treatment to be funded. Obviously I'm speaking as someone from the UK, where we don't just allow people to die if they don't have enough money to afford care. How the USA will approach this will be interesting.

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So if I understand, in the case of genetic metabolic disorders, introducing the missing metabolic function to modified blood cells helps support non modified cells. Do the toxic compounds move from the native cells to the modified cells where they are properly processed?

Do you know where we are in terms of safety for gene therapy?

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It really depends on the specific disease and the mechanisms that causes damage to brain cells, but in some cases yes. For most of those disease the toxic compounds will be secreted from the cells, so they are in the extracellular space were the modified cells can take them up and process them.

Gene therapy is not my area of expertise, so someone else might be more up to date on this. The major risk of gene therapy is that the insertion/editing of a gene will lead to unintended disruption of other genes, which worse case scenario might make them more likely to become cancerous. The method used for this treatment, ex vivo gene therapy, were the gene therapy is performed outside of the body is more safe as it allows for extra checks on the cells before they are transplanted back into the patient.

Thanks, we do live in interesting times.

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The disease is not caused by ARSA deficiency in leukocytes specifically though, but rather by ARSA deficiency in all cells that lead to sulfatide accumulation that is more toxic for specific organs/cell types, like the brain and the galbladder. The bone marrow transplantations works because the blood derived cells will migrate into the brain and breakdown the excessive sulfatides in the extracellular space.