Gene-editing Treatment Relieves Debilitating Symptoms

Kiwi patients with a painful and debilitating
inherited illness say gene-editing therapy has changed their
lives.

Kiwi patients with a painful and
debilitating inherited illness say gene-editing therapy has
changed their lives and completely relieved their
symptoms.

The group of seven patients who participated
in a clinical trial have hereditary angioedema, meaning they
formerly experienced unpredictable, sometimes frequent and
potentially lethal attacks of swelling.

They were
treated in late 2021 and early 2022 in the New Zealand
Clinical Research facility in Auckland, as part of a
first-in-human clinical trial of the CRISPR-Cas9
gene-editing therapy.

“It looks as if the
single-dose treatment will provide a permanent cure for my
hereditary angioedema patients’ very disabling
symptoms,” says principal investigator Honorary Senior
Lecturer Dr Hilary Longhurst. “Plus, of course, there is
huge potential for development of similar CRISPR-Cas9
treatments for other genetic disorders.”

People with
hereditary angioedema find the attacks of swelling impact on
their ability to take up normal opportunities in work and
life.

The attacks may occur several times a week or a
few times a year.

Over a lifetime, the disorder is
associated with significant anxiety and
depression.

The patients who participated in the trial
are reporting that the therapy has been “life-changing”,
says Dr Longhurst.

“Many of the patients have had
family members who have died and they are absolutely
terrified,” Dr Longhurst says. “They are frightened both
of the pain of abdominal attacks, which is comparable to
that of heart attacks and childbirth, but also the fact
their airways might swell up and they might
suffocate.”

Globally, it is estimated one in 50,000
people have the hereditary angioedema, which means it is
likely 100 New Zealanders have the condition. However,
because it is rare, it is often not correctly diagnosed. So
far only around 60 Kiwi patients have been
identified.

Patients have an inherited deficiency of
the C1 inhibitor protein, which controls a biochemical
pathway linked to inflammation. Without sufficient C1
inhibitor, the body gets a build-up of a protein fragment
(peptide) called bradykinin, which stimulates
swelling.

The therapy is delivered via a lipid
nanoparticle, or miniscule ball of fat, containing the
CRISPR-Cas9 genetic material, and is infused through a vein
in the patient’s arm over two to four hours.

“This
ball of lipid targets the treatment into the liver, and then
the CRISPR guides the Cas9 onto exactly the gene that is
causing the problem,” Dr Longhurst says.

The gene,
KLKB1, produces a protein precursor to bradykinin,
called kallikrein.

“The CAS9 acts as a molecular
scissor to cut the KLKB1 gene. The body heals the
break in the KLKB1 gene, but in doing this it sows
additional bits of genetic material so that gene doesn’t
work anymore.

“The effect of the treatment is to
silence the KLKB1 gene and to prevent overproduction
of the kallikrein and bradykinin that cause the
swelling.

“I always warn the patients that they may
feel fluey on the day of the treatment but in fact the
symptoms have been minimal,” Dr Longhurst says. “Some
people feel a bit tired or have a headache, and one person
had a bit of a temperature that lasted a few minutes. It’s
been incredibly well tolerated.”

After a single
treatment, the patients either had no more attacks of
swelling or a dramatic reduction and then cessation of
attacks after a few weeks.

“One patient, who had
been experiencing frequent severe attacks, took a while to
settle down, but most were immediately attack-free,” says
Dr Longhurst.

By January 2023, ten months 14 months
after the first treatment, almost all the patients have been
free of attacks for between two and ten months and all
patients have been able to stop their previous angioedema
medications. The exception was a minor hand swelling after a
sports injury, which technically classified as a potential
angioedema.

Dr Longhurst, an Honorary Associate
Professor of Medicine at the University of Auckland,
presented results from the trial at a November meeting of
the American College of Allergy, Asthma and Immunology, with
the abstract published in the Annals
of Allergy, Asthma & Allergy (November
2022)
.

The US company, Intellia Therapeutics,
chose New Zealand for the first-in-world trial as the
country had relatively little Covid-19 at the time, late
2021.

Since the New Zealand trial, family members of
participants and patients in the Netherlands and the UK have
received the same treatment.

The next stage will be a
randomised, double-blinded, placebo-controlled
trial.

© Scoop Media


 

Read more here: Source link