Gene therapy to 'correct' the white blood cells of 'bubble children'

• A bubble boy is cured after being diagnosed with the heel prick

We all understood the importance of contact when we couldn't have it in confinement and much of the Covid pandemic.

Let's imagine that this isolation began from the moment we were born and we could only have contact with others through plastic.

It is the story of David Vetter, a boy who was born in 1971 in the USA with

), a rare hereditary disease (around one case per 35,000-50,000 births) that it

causes

(the white blood cells that protect the body from viruses, bacteria, and other pathogens).

There are several types of SCID, in some it is linked to the X chromosome (the form that Vetter had) and in others it is due to mutations in a gene that prevents them from producing certain vital proteins in the formation, function or organization of lymphocytes (for example , adenosine deaminase).

For this reason,

, their immune system cannot deal with infections, so it

.

Aware of this, the doctors prepared a special chamber, a kind of plastic bubble with sterilized air (hence the disease is also known as

) where they put Vetter as soon as he was born, without passing by the arms of his mother.

His whole life was reduced to that bubble, he ate, played, slept inside that little world, which was conceived as something temporary while they found a compatible bone marrow donor or a cure for the disease.

Even

remaining isolated.

But Vetter didn't come out of his bubble until near the end of his life, at age 12.

Until now, the treatment for this disease was

(or umbilical cord blood), having a better chance of working if it is performed in the first three months of life (which is why

or heel pricks are so important, to diagnose it from the beginning and not wait for the child to have infections and deteriorate).

The ideal donor is a brother or sister of the patient.

But

and around one third of children with SCID develop immune problems years after the transplant.

Gene

has become the

for these children to get out of that 'bubble'.

In recent years, several studies of this technique applied to children with SCID have been carried out, which are bearing fruit.

This is the case of the work published this Wednesday by

, carried out by a team led by Morton J. Cowan, medical director of the Pediatric Cell Therapy Laboratory at the University of California, San Francisco and an expert in these severe combined immunodeficiencies. .

This phase I-II work (

) focuses on

, an enzyme essential for the development and function of T and B lymphocytes whose deficiency is due to mutations in the DCLRE1C gene.

This type of SCID

(allogeneic hematopoietic or 'blood-forming' cell transplantation) and is more difficult to treat due to other associated complications since

of double chain.

Other types of SCID have already been successfully treated with

(ie, with the patient's own transplant) and this study applies it in SCID with Artemisia deficiency.

To this end

who did not have compatible siblings for a hematopoietic cell transplant were followed up

, with monthly follow-up for the first six months and quarterly for up to 24 months (median follow-up of 31.2 months). ).

Basically, what they did is

(autologous CD34+ cells, CD34 is a marker of these hematopoietic cells),

that has the mutation, and

( lentivirus, in this case) but it is effective penetrating cells, so when it enters diseased hematopoietic cells it transfers the correct gene to them.

These cells are stored frozen and after the patient receives conditioning (in this case with the drug busulfan at low doses) these cells are transfused, that is,

into his body and they go to the bone marrow. , divide and create copies,

for the child where there are B and T cells.

One of the problems with gene therapy for these patients is that when some types of SCID were started in the early 2000s they caused leukemia, but it was due to the type of virus used to carry the corrected gene.

With the new vectors introduced, the researchers believe that it is very difficult for this to happen, although monitoring must be maintained.

In fact, in this study

, there were no serious adverse effects, and the results show

and

.

In the study the authors note: "This approach restored immunity and was safe (within the context of disease and alternative approaches) and we conclude that further study is warranted."

Similar or better results and less toxicity

In statements to SMC assessing this study, Pere Soler Palacín, head of the Pediatric Infectious Pathology and Immunodeficiency Unit of the Vall d'Hebron Children's Hospital in Barcelona, ​​stresses that it is "excellent work carried out by a leading team in the field ".

Soler points out that

, "in entities as infrequent as this type of severe combined immunodeficiency (SCID)

".

This work, highlights Soler, adds another SCID to the group of primary immunodeficiencies that can be treated by gene therapy.

"This technique, when it works correctly as in this case, usually provides

, by not infusing "foreign" cells to the patient but by genetically modifying their own cells."

For the specialist, "an important theme of the study is that practically all the patients included had been diagnosed through neonatal screening, so gene therapy was applied in patients free of complications of their disease. This point further reinforces the importance of the neonatal screening-gene therapy binomial in the treatment of these and other genetic diseases".

The main limitation of the study for Soler is "

, because for the rest of SCDI with different genetic defects, studies with the same characteristics will have to be carried out."

The Vall d'Hebron specialist adds that, as the authors comment, a longer follow-up is needed to determine the benefit of the treatment in the non-immunological defects of this disease.

For his part, Luis Ignacio González Granado, a medical specialist in immunodeficiencies and associate professor of pediatrics at the Complutense University of Madrid, ensures that

and in line with clinical trials of gene therapy in this group of diseases.

"The study design consists of two phases. In the first, the success of the treatment is measured by the safe administration of the modified cells and the safe use of busulfan, 42 days after the infusion.

and some reconstitution conditions derived from the introduction of the vector into the cells in this type of assay, in addition to the transduction efficiency.

The second measure of treatment success, already in the second stage, measures the

."

Recovery of T, B and 'natural killer' lymphocytes

González Granado adds that from the point of view of efficacy, "assessed in terms of immunological reconstitution, the study

] lymphocytes. In four out of six cases, patients became independent of the administration of gamma globulin (at 24 months of follow-up), necessary in the period prior to treatment to avoid serious infections. This result is equal to or superior to that obtained by hematopoietic progenitor transplantation".

The professor also criticizes him: "The high rate of autoimmune hemolytic anemia (four out of nine at one year of follow-up) requires long-term follow-up of this complication, probably more related to the underlying disease (it is a possible complication of SCID, as occurs in the X-linked severe combined immunodeficiency subtype), as the authors acknowledge in terms of limitations at the end of the article, than with the gene therapy procedure."

But, summarizing, González Granado points out that the work "constitutes

with this type of disease in particular. What does it mean for children in our country that they can present this disease? Despite the fact that the birth screening strategy -along with the rest of the endocrine-metabolic tests- has been shown to be cost-effective, in our country it

since 2017. Several autonomous communities have expressed their interest or have recently implemented it in their legislation as a step prior to de facto implementation."

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