Gene Therapy Halts Progression of Cerebral ALD
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Gene Therapy Halts Progression of Cerebral ALD

Team Representative:
Florian Eichler, MD
Associate Professor of Neurology, Harvard Medical School; Director, Center for Rare Neurological Diseases, Massachusetts General Hospital 
Phone: 617-724-7121

Media Contact:
Michael Morrison
Phone: 617-724-6425

Summary of findings in layman's terms:

Researchers used a lentivirus to infuse a normal copy of the ABCD1 gene into the bone marrow of boys with cerebral adrenoleukodystrophy (ALD), and the corrected protein stopped disease progression. This is the first successful gene therapy treatment to halt a fatal brain disease.

ALD affects 30 to 40 percent of boys between 4 and 8 years old who are born with a mutation in the X-linked ATP-binding cassette, subfamily D, member 1 (ABCD1) gene. The boys with ALD quickly begin to lose their ability to walk and talk. By the time a diagnosis is suspected, a brain scan shows a massive lesion in white matter tracts.

For the study, the researchers infused the boys' autologous hematopoietic stem cells with a lentivirus vector, Lenti-D, which delivered a normal copy of the ABCD1 gene when infused back into the bone marrow. The corrected protein was expressed in 20 percent of the peripheral blood cells in the boys, which appeared to be enough to stop disease progression.

The boys, whose average age was 6 years old, were identified through screening and family history. They were asymptomatic at the time of the transplant but had evidence of early white matter inflammation on a magnetic resonance imaging (MRI) scan.

Fifteen of 17 boys with cerebral ALD are doing well. One patient in the study died from disease progression. In hindsight, his disease had been advancing more rapidly at the time of enrollment. Another patient withdrew from the study after the transplant, and his parents decided to have him undergo allogeneic bone marrow transplant. He too died.

The boys are being closely followed. MRI scans show that the early lesions have stopped spreading. There haven't been any engraftment problems or graft-versus-host issues. The 15 boys have minimal or no symptoms and are leading normal lives two years later. 

Specific biological innovation of study: 

The safe and effective delivery of genetically modified hematopoetic stem cells represents biological innovation by demonstrating that genetic modification of cells in the myeloid compartment has a profound impact upon the brain. 

Previously the long-term benefits of hematopoietic stem-cell transplantation in cerebral adrenoleukodystrophy (ALD) are thought to be mediated by donor-derived replacement of myeloid derived cells, possibly including microglial cells. However, this study demonstrates that genetic correction of CD34+ bone marrow cells can alter brain inflammation in ALD. The study thereby sheds light on the cross talk between the brain and the hematopoetic system, pointing to biological innovation arising from interdisciplinary collaborations.

Further innovation arises from the effective use of brain imaging as a biomarker of disease progression. By selecting patients with early inflammatory disease, evident by gadolinium enhancement on MRI, the investigators recognized a window of intervention crucial for effective treatment.

The study represents a milestone not just for ALD but for the field of neurodegeneration at large. For many years, gene therapy has shown great promise, but clinical applications have always seemed just beyond the horizon. Today, Lenti-D therapy appears to be poised as a real treatment option for cerebral ALD and opens the door to other neurological diseases where bone marrow transplantation is currently used.

Potential impact on patient care and/or how the findings contributed to an improved understanding

Untreated cerebral adrenoleukodystrophy (ALD) leads to severe disability or death approximately 2 years after its onset. During the 1990s, it was discovered that stabilization of cerebral ALD lesions may occur 6 to 12 months after successful allogeneic hematopoietic stem-cell transplantation. This is currently the only effective treatment but it only helps patients who have early-stage cerebral ALD and comes at the cost of multiple complications. 

An important impact of the Hematopoietic Stem-Cell Gene Therapy described in the paper, is that it allows for the use of autologous CD34+ cells, thereby avoiding complications associated with allogeneic transplantation. This has great impact on patient care as over the past few decades many patients have suffered from engraftment problems and graft versus host disease associated with allogeneic transplantation. Now patients without a matched sibling donor can be safely and effectively treated. 

An important reason for nominating this study for the Top Ten Clinical Research Award has been due to the hopes and prospects the study has raised. The findings suggest that gene therapy can have a positive impact on the lives of patients. For many years, gene therapy had shown great promise, but clinical applications and their impact upon patient lives always appeared out of reach. Today, this study presents tangible progress for patients with a devastating genetic brain disease and opens the door for application to other neurological diseases that are treatable with hematopoietic stem-cell transplantation.

By presenting a safe and effective delivery method of genetically modified hematopoetic stem cells, the study has improved our understanding of ALD and the cross-talk between the brain and the hematopoetic system. It will further impact patient care as newborn screening for ALD is now being implemented across the United States. Early stage diagnosis will thus be met by targeted therapy and suggests a model for precision medicine of the future. 

Journal citation:

Eichler F, Duncan C, Musolino PL, Orchard PJ, De Oliveira S, Thrasher AJ, Armant M, Dansereau C, Lund TC, Miller WP, Raymond GV, Sankar R, Shah AJ, Sevin C, Gaspar HB, Gissen P, Amartino H, Bratkovic D, Smith NJC, Paker AM, Shamir E, O'Meara T, Davidson D, Aubourg P, Williams DA.

Hematopoietic Stem-Cell Gene Therapy for Cerebral Adrenoleukodystrophy. N Engl J Med. 2017 Oct 26;377(17):1630-1638.