People living with HIV will be treated with genetically engineered stem cells next month by the team of Nobel Prize-winning immunologist David Baltimore.
The goal: to create, in patients, new immune systems resistant to HIV.
“We are very hopeful we can use that as a way of effectively curing patients, and allowing them to live drug-free lives,” Baltimore told the World Science Festival in New York on May 31.
The trial, which blends techniques both conjured in the lab and pilfered from nature, is long-awaited. Baltimore calls it a “Hail Mary Pass.” Like trials sponsored by Sangamo Biosciences, it was partly inspired by the “Berlin Patient” Timothy Brown.
A leukemia patient, Brown needed a bone marrow stem-cell transplant to replace his blood cells with those of a donor. Because he also had HIV, his doctor gave him bone marrow cells that were an immunological match, with a twist: they were from a donor who was one of the 1% of the European population resistant to HIV.
Brown’s HIV vanished. It has not returned in six years.
In a series of ongoing Sangamo trials, scientists have been disarming the gene that made Brown and the 1% resistant: the CCR5 gene coding for a receptor on CD4 T cells through which the virus enters. HIV-resistant people have two copies of the defective CCR5 gene. Sangamo has been removing patient blood cells; disarming CCR5 in their CD4 T cells (by slipping disruptive “zinc finger nucleases” (ZFNs) into their genomes via different techniques, including adenoviral vectors); returning the cells. (See related Drug Discovery and Development story here.)
Some preliminary results have been highly encouraging. But some experts say the key to long-term success may lie in altering CCR5 in stem cells, permanent cells of the bone marrow, which mature into—and give the body—a lifetime coterie of blood cells, including T cells. For that reason, many groups are now disarming CCR5 in stem cell pre-clinical work.1
Baltimore’s group will bring it to patients in July, via the company he co-founded in 2007: Calimmune. The company was formed around the stem cell approach, devised by the teams of Baltimore and UCLA AIDS Institute Director Irvin Chen.
Like Sangamo, Calimmune will disarm CCR5 in CD4 T cells. But—in addition to adding another gene—Calimmune is also disarming CCR5 in stem cells. The hope: CCR5-disabled stem cells will pump out a rainbow of HIV-resistant blood cells—and create entire HIV-resistant immune systems—to protect patients for life.
Other differences are that Calimmune is disarming CCR5 using a different tack—not ZFNs delivered by adenoviral vectors (and other techniques), but natural hairpin RNAs delivered by lentiviral vectors.2, 3 And it is goosing resistance by adding a gene coding for a protein (C46) that inhibits HIV binding ability.
The approach is in part a “Hail Mary Pass” because of the viral vectors. Viral vectors are viruses whose dangerous segments are removed, but retain their ability to infiltrate DNA. New therapeutic genes are loaded on these vectors, and hitch a ride into patients’ cells. But sometimes such vectors can insert themselves into the wrong genome segments, causing cancers. Sangamo and Calimmune are using comparatively safe viruses. Still, all patients need to be watched carefully.
And while Sangamo’s approach is complex, Calimmune’s is more so (as it both disarms a gene and adds one).
But Calimmune’s final product renders mice HIV-free for a lifetime, said Baltimore, chairman of Calimmune’s Board of Directors. The logic of this helped his crew—which includes former Johnson & Johnson staffers, and Berlin Patient doctor Gero Hutter—score a $20 million grant from the California Institute for Regenerative Medicine (CIRM), the largest stem cell funding body in the world.
The CIRM reviewer summary said of Calimmune’s HIV work:
“The resources and investigators are outstanding and the team is superb, both scientifically and in therapy development. The Disease Team comprises a collaboration between two complementary groups, one academic and one corporate. Each brings unique expertise to the project, with the academic group providing scientific know-how and proof of concept, and the corporate group providing expertise in biologics development and commercialization. The team leaders are accomplished, highly productive investigators with a demonstrated track record in the field of HIV research, gene therapy, and/or clinical drug development. Key members of this team….demonstrated proof of concept in tissue culture and relevant models....The principal investigator has built up a rich and well-considered network of collaborations and resources and there is no doubt that the environment will be sufficient for this task.”
But CIRM also said: “Another reviewer expressed the view that although the treatment will likely find a significant niche, the complexity, cost and potential toxicity of the approach will likely limit its use, even if successful.”
Still, an even more complex approach has generated good news. That approach, offered in a small City of Hope clinical trial also targeting CCR5 in stem cells via lentiviral vector, was declared safe in 2010. Four patients with AIDS-related lymphoma were given stem cells genetically engineered in three ways to be resistant to HIV: by suppressing viral replication and function, and again, disabling CCR5 (if via a different method).4
While the approach was deemed safe, and the altered genes persevered, they did not do so in large numbers. Patients didn’t exhibit therapeutic levels several months out. More stem cells needed to be genetically altered, investigators said.
But Baltimore said by email that Calimmune has been watching all these clinical and preclinical trials. “We have learned a tremendous amount from the research conducted by our colleagues in this field, including City of Hope.”
1. Holt N, et al. “Zinc Finger Nuclease-Mediated CCR5 Knockout Hematopoietic Stem Cell Transplantation Controls HIV-1 In Vivo,” Nature Biotechnology, Vol. 28, Iss 8, August 2010: p839-847.
2. Shimizu, S., et al. “A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model,” Blood, Vol. 115, Iss 8, February 25, 2010: p1534-1544.
3. Liang, M., et al. “Inhibition of HIV-1 infection by a unique short hairpin RNA to chemokine receptor 5 delivered into macrophages through hematopoietic progenitor cell transduction,” Journal of Genetic Medicine, Vol 12, Iss 3, March 2010: p255-265.
4. DiGiusto, D.L. “RNA-based Gene Therapy for HIV Using Lentiviral Vector-Modified CD34+ Cells in Patients Undergoing Autologous Stem Cell Transplantation for AIDS-Related Lymphoma," Science Translational Medicine, Vol 2, Iss 36, June 16, 2010: p36ra43.