New Scientist - USA (2022-06-04)

20 | New Scientist | 4 June 2022

CHILDREN with some rare genetic

conditions who would once have

died at just a few years old could

now have typical life expectancies

due to gene-replacement therapy.

“We’re curing kids of fatal

diseases. It’s wonderful,” says

Donald Kohn at the University

of California, Los Angeles.

Kohn and his colleagues are

trialling a gene therapy – in

which disease-causing versions

of genes are replaced by normally

functioning versions – for

leukocyte adhesion deficiency

type-1 (LAD-1).

This rare condition occurs when

immune cells called leukocytes

can’t travel to the site of a wound

or injury, causing otherwise

benign skin infections to become

chronic. LAD-1 usually results in

death before the age of 2, unless

the child has a stem cell

transplant.

The gene therapy works by

replacing a mutated version of the

ITGB2 gene, which is responsible

for LAD-1. Kohn and his colleagues

take a child’s stem cells from bone

marrow and insert regular copies

of the ITGB2 gene using a virus

that has been modified not to

cause harm. They then use a

low dose of chemotherapy to

destroy the remaining bone

marrow, and return the edited

cells back into the child.

Since 2019, nine children have

received ITGB2-replacement

therapy, with their age at the

initiation of treatment ranging

from 5 months to 9 years. Now,

none of those children experience

chronic skin or lung infections

and “they’re leading normal lives,

they’re in school, they’re off all

their antibiotics”, says Kohn.

This is just one promising

clinical trial result for several

gene-replacement therapies

presented at the annual meeting 

of the American Society of

Gene and Cell Therapy, held in

Washington DC from 16 to 19 May.

Ewelina Mamcarz from St. Jude

Children’s Research Hospital in

Memphis, Tennessee, presented

positive results for a gene therapy

for X-linked severe combined

immunodeficiency (X-SCID),

another rare immune condition

that is usually fatal before the age

of 2 without a stem cell transplant.

X-SCID is sometimes known

as “bubble boy disease”,

because it only affects males,

with these children previously

having to isolate in plastic

chambers to avoid infections.

This therapy replaces the

abnormal version of the IL2RG

gene that causes the condition,

similarly using a virus to deliver

normal copies of the gene

into stem cells.

Since 2016, 23 infants with

X-SCID have received the

therapy when aged between

2 months and 14 months. All have

now developed fully functional

immune systems or are expected

to as their treatment progresses,

says Mamcarz. “They’re all home

with their families and they’re no

different to other kids,” she says.

A gene therapy for another

rare condition, infantile

GM1 gangliosidosis – which

progressively destroys nerve

cells and is usually fatal before

the age of 10 – was presented

by David Weinstein from the

US company Passage Bio.

Two children, aged 15 months

and 31 months at treatment,

received the therapy in March

2021. To replace the abnormal
      version of the GLB1 gene
      causing their condition,
      Weinstein’s team injected
      normal copies of the gene via
      a virus into cerebrospinal fluid
      in the backs of the children’s
      necks. The virus then circulated
      around their brains and spinal
      cords, delivering the new genes.

The brains of children with

GM1 gangliosidosis usually

progressively shrink, but the

younger child has displayed

normal brain growth since

the gene therapy. Both have also

learned to walk and talk, which

only some children with the

condition ever achieve and they

then lose the ability as their illness

progresses. The older child has

shown improvements, but not

to the same extent as the younger

one, possibly because he had

more severe disease to begin with.

No side effects

None of the three gene therapies

has caused any serious side effects

to date. The only known treatment

with the same effectiveness is a

stem cell transplant. This requires

a matched donor, which can be

hard to find.

Stem cell transplants also run

the risk of graft-versus-host

disease, a potentially life-

threatening complication that

occurs when the transplanted cells

attack the recipient’s own cells.

In the early 2000s, gene

therapies fell out of favour after

some people receiving them

developed leukaemia, but this

was related to the particular

mouse virus used to deliver the

genes into cells, says Mamcarz.

Most groups now use an

inactivated form of HIV to deliver

the genes. It has been gutted so

“it’s just like a shell for carrying the

genes into cells”, says Mamcarz.

The treatment seems safe so

far and there is no risk of them

catching HIV from the inactive

virus. However, all children who

receive this virus will be carefully

monitored for at least 15 years to

check for increased cancer risk,

which is a requirement of the

US Food and Drug Administration

for all gene therapies.  ❚

“ They’re all home

with their families

and they’re no

different to other kids”

Health

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Gene therapy on the rise

Having fallen out of favour in the 2000s, gene therapy is now helping children

who would otherwise have died at a young age, reports Alice Klein

Gene therapy works

by replacing sections

of DNA in the body

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