Experimental gene therapy reverses sickle cell disease for years

Date:
December 13, 2021
Source:
Columbia University Irving Medical Center
Summary:
An experimental gene therapy for sickle cell disease restored blood
cells to their normal shape and eliminated severe pain crises for
years after treatment, a multicenter study has found.



FULL STORY ==========================================================================
A study of an investigational gene therapy for sickle cell disease has
found that a single dose restored blood cells to their normal shape and eliminated the most serious complication of the disease for at least
three years in some patients.


==========================================================================
Four patients at NewYork-Presbyterian/Columbia University Irving Medical
Center participated in the multicenter study, the first to report on
such long-term outcomes of a sickle cell gene therapy. The study was
published online December 12 in the New England Journal of Medicine with
John F. Tisdale, MD, senior investigator at the NIH's National Heart,
Lung and Blood Institute, as corresponding author.

The single-dose therapy, tested on 35 adults and adolescents with sickle
cell disease, essentially corrected the shape of the patient's red
blood cells, but also completely eliminated episodes of severe pain,
caused when rigid, crescent-shaped red blood cells clump together and
block blood vessels. The painful episodes often result in widespread
organ damage. Such episodes are a frequent cause of emergency department
visits and hospitalizations and lead to early death.

"You cannot overstate the potential impact of this new therapy," said
Markus Y.

Mapara, MD, PhD, professor of medicine at Columbia University Vagelos
College of Physicians and Surgeons and a co-author of the study. "People
with sickle cell disease live in constant fear of the next pain
crisis. This treatment could give people with this disease their life
back. We hope this therapy will also be successful in younger patients
so they can grow up without experiencing pain crises and live longer."
Sickle cell disease is caused by mutations in the beta-globin gene,
leading to the production of abnormal hemoglobin, the oxygen-carrying
molecule in red blood cells. Normal red blood cells are shaped like
donuts, but in sickle cell disease, the abnormal hemoglobin causes red
blood cells to stiffen and adopt a spiky, sickle-like shape. The disease
is estimated to affect 100,000 people in the United States and is more
common among Black Americans. Sickle cell disease can be cured with a
donor bone marrow transplant but use of this therapy has the best chance
of success in patients with a closely matched sibling donor, which is
only a minority of patients. Median lifespan for patients with sickle
cell disease still remains in their 40s.

With the new gene therapy, called LentiGlobin, blood-forming stem cells
are collected from the patient's blood. Harmless lentiviruses are then
used to deliver a modified copy of the beta-globin gene into the stem
cells. When the cells are later reinfused into the patient, they take up residence in the bone marrow and start making healthy new red blood cells.

In the clinical trial the therapy completely eliminated severe pain crises
in the months following infusion (follow-up ranged from 4 to 38 months)
-- the longest period in which a gene therapy for sickle cell disease
has been studied.

"The effects have been sustained throughout the trial period, which
suggests that the results may be durable," says Mapara, who is also the director of the Bone Marrow Transplantation and Cell Therapy Program at NewYork-Presbyterian/ Columbia University Irving Medical Center.

Because LentiGlobin uses a patient's own stem cells, there's no risk of rejection, a common complication of conventional bone marrow transplants, Mapara adds.

One limitation of the gene therapy is that patients must first be treated
with high-dose chemotherapy to eliminate old stem cells and make room for
the modified stem cells, a process known as conditioning. Chemotherapy can
be toxic and is associated with a small risk of cancer. Two patients in
the trial developed leukemia, which the researchers suspect was related
to the chemotherapy, not to LentiGlobin treatment.

Researchers are currently working on less toxic approaches to conditioning
the bone marrow before gene therapy. "The eventual goal will be to
give this treatment as early as possible, well before patients develop
organ damage and other complications of sickle cell disease," says
Mapara. "But before we can do this, we need to find a safer alternative
to chemotherapy for conditioning strategies, such as antibodies." NewYork-Presbyterian/Columbia University Irving Medical Center is one
of the few centers in the world participating in gene therapy clinical
trials for sickle cell disease. In addition, investigators at Columbia
are hoping to identify strategies to make gene therapies for sickle cell disease financially attainable.

========================================================================== Story Source: Materials provided by
Columbia_University_Irving_Medical_Center. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Julie Kanter, Mark C. Walters, Lakshmanan Krishnamurti, Markus
Y. Mapara,
Janet L. Kwiatkowski, Stacey Rifkin-Zenenberg, Banu Aygun,
Kimberly A.

Kasow, Francis J. Pierciey, Melissa Bonner, Alex Miller, Xinyan
Zhang, Jessie Lynch, Dennis Kim, Jean-Antoine Ribeil, Mohammed
Asmal, Sunita Goyal, Alexis A. Thompson, John F. Tisdale. Biologic
and Clinical Efficacy of LentiGlobin for Sickle Cell Disease. New
England Journal of Medicine, 2021; DOI: 10.1056/NEJMoa2117175 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/12/211213160126.htm

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