Gene therapy restores immunity in infants with rare immunodeficiency disease

Modesto Morganelli
Aprile 21, 2019

One infant had little response initially but a second dose of gene-corrected bone marrow stem cells (given without chemotherapy preconditioning) normalized T cell levels and, like the other recipients, cleared preexisting infections and is growing normally, Ewelina Mamcarz, MD, of St. Jude Children's Research Hospital in Memphis, Tennessee, and colleagues reported in the New England Journal of Medicine.

All have normal growth and development, and any infections they had suffered due to their disabled immune system have disappeared.

Three months after treatment, non-defective immune cells appeared in all but one of the treated children. This, they hoped, would stop the treatment from inadvertently causing leukemia by stumbling across a cancer-causing gene and activating it. "Our patients are able to generate a healthy, fully-functional immune system and are now responding to vaccinations, and that's a first for a gene therapy trial".

"This is the best we have so far for gene therapy".

Current treatment involves a bone marrow transplant from a tissue-matched sibling donor.

After the new treatment, which is combined with chemotherapy to help the edited DNA to multiply once inside the patient's body, most patients were able to leave the hospital within a month. The cells were then frozen and underwent quality testing.

The idea of gene therapy is to introduce, remove or change the genetic material in cells to treat a specific disease.

Merlin Crossley, professor of molecular biology at the University of New South Wales, added that getting a matched donor for stem cell transplants had always been hard, and that gene therapy was a promising alternative. None has developed a life-threatening infection since receiving gene therapy, an indication of treatment effectiveness. "All the active parts of the virus have been taken out with only a shell remaining". The virus inserts an undamaged copy of the IL2RG gene into the cells. We believe that this type of virus is safer and more effective for gene therapy.

Also, the effect appears to be more durable with the new design, she noted. Now they are home, living normal lives, attending daycare.

This new therapy uses a genetically altered virus to infect stem cells in bone marrow collected from the babies.

Importantly, the virus also included "insulators" to block activation of genes adjacent to the location where IL2RG is inserted into patient's DNA, the researchers said.

But that has turned around, she said.

Those children, treated when they were 2 to 14 months old, have only been followed for 7 to 25 months, so further study will be needed to determine if there are any long-term problems.

In the study, there were only low-grade acute toxic effects during a median follow-up of 16 months.

"In the original studies, leukaemia developed within about 12 to 15 months". We have not observed clonal evolution in the patients we have treated.

Gene therapy has been used successfully over the past decade. Dr. Malech co-led the development of the lentiviral gene therapy approach with St. Jude's Brian Sorrentino, M.D., who died in late 2018.

The best treatment for the disease so far had been a bone marrow transplant from a matched sibling donor, but more than 4 of 5 babies with SCID-X1 lack such donors, Mamcarz said. Lentiviral gene therapy with low dose busulfan for infants with X-SCID.

"A simple infection like the common cold could be fatal", Mamcarz said.

The other authors are Sheng Zhou, Timothy Lockey, Hossam Abdelsamed, Shane Cross, Guolian Kang, Zhijun Ma, Jose Condori, Jola Dowdy, Brandon Triplett, Chen Li, Gabriela Maron, Xing Tang, William Janssen, Byoung Ryu, Mitchell Weiss, Benjamin Youngblood and Michael Meagher, all of St. Jude; Juan Carlos Aldave Becerra of Hospital Nacional Edgardo Rebagliati Martins, Peru; Joseph Church, Children's Hospital Los Angeles; Elif Dokmeci, University of New Mexico; James Love, University of Oklahoma Health Sciences Center, Tulsa; Ana Carolina da Matta Ain, University of Taubaté, Brazil; Hedi van der Watt, Copperfield Childcare, Claremont, South Africa; Suk See De Ravin and Harry Malech, both of the National Institute of Allergy and Infectious Diseases; and Janel Long-Boyle and Jennifer Puck of UCSF.

Gene therapy developed at St. Jude Children's Research Hospital has cured infants born with X-linked severe combined immunodeficiency (SCID-X1).

The gene therapy trial in infants is funded by the American Lebanese Syrian Associated Charities (ALSAC), and by grants from the California Institute of Regenerative Medicine and the National Heart, Lung, and Blood Institute, part of NIH, under award number HL053749.

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