In early March 2011, we gave a brief history of HIV treatments. The article has also referred to recent studies demonstrating that early treatment with highly active antiretroviral therapy (HAART) further improves survival of asymptomatic patients with higher CD4+ T cell counts. Instead of fading away as many studies do, these studies were accompanied with parallel studies demonstrating that the prophylactic use of HAART succeeded in shielding exposed individuals from contracting HIV. These studies, no doubt, were favorable to Gilead Sciences (GILD), as demonstrated in the stock’s recent performance. What makes this news important is the fact that sustained treatment with these drugs for to avert the reactivation of the virus and the progression of AIDS subjects the patients to dangerous adverse effects and the drugs to the risk of viral resistance.
The aim of the March article was to introduce a new approach developed by Sangamo (SGMO), which could amount to a kind of cure for HIV infection in case the same results are reached in future trials. In the HIV/AIDS approach, Sangamo used its ZFN-mediated editing technology to cause the same mutation in CCR5 that made individuals largely resistant to the most common strain of HIV. Sangamo’s scientists removed CD4+ T cells from the blood of HIV-infected subjects and treated them with its ZFNs that modify the DNA sequence encoding the CCR5 gene. The process did, indeed, generate CCR5-modified autologous T-cell product (SB-728-T), which was infused in HIV/AIDS patients. Five of six treated subjects exhibited sustained improvements in their CD4:CD8 T cell ratio, suggesting that the cells were resistant to HIV infection. The data offered an initial validation of Sangamo’s gene modification approach. They provided hope for a possible more sustainable treatment for HIV.
A couple of days ago, another study published in the Proceedings of the National Academy of Sciences (PNAS) demonstrated the successful use of Sangamo’s zinc finger nucleases (ZFNs) to produce genetically modified pigs. The study provided another validation of the firm’s gene-editing technology. The approach brings a significant advancement in the development of improved, less immunogenic animal tissue - a new source for tissue and organ transplant into humans.
Organ transplantation has become a successful clinical discipline indispensable for thousands of patients with organ failures that threaten their survival. A major unsolved problem in the transplantation process is the shortage in the supply of appropriate tissues and organs. Sangamo’s ZFNs approach, which seems successful in knocking out any targeted gene in the pig, has proven capable of supplying less immunogenic pig organs. The firm’s scientists and their collaborators in the laboratory of Prof. Dr. Heiner Niemann of the Institute of Farm Animal Genetics in Germany knocked out both copies of the 1,3-galactosyl transferase (GGTA-1) gene from pig cells which led to significantly improved organ survival in a pig-to-baboon organ transplantation model.
More proof of concept has come also at the hands of firms that licensed ZNF technology for other than clinical purposes. Sigma-Aldrich and Dow AgroSciences have used the technology in lab research, transgenic animals and commercial production of cell lines. They marketed their products based on Sangamo’s technology. Sigma-Aldrich has marketed ZFN-derived gene editing tools for commercial production of protein pharmaceuticals.
Sangamo has retained the rights to deliver ZFP TFs or ZFNs into human or animals for diagnostic, therapeutic, or prophylactic purposes.
With those proofs of concept and clinical utility, ZFP Therapeutics are seen capable of addressing unmet medical needs in a number of chronic debilitating diseases. Richard Insel, M.D. Chief Scientific Officer for the Juvenile Diabetes Research Foundation (JDRF) who was not associated with the pig study said, "In the example of type 1 diabetes, pancreatic islets can be replaced by transplanting functioning ones into a patient. However, we face a severe shortage of human cadaver organs in the U.S. and cannot satisfy the transplantation needs of people with the disease. Using ZFN-modified pigs as a source of tissues for human transplantation may prove to be a promising solution to the shortage of donated human organs for diabetes and other diseases."
JDRF has helped pioneer islet cell transplantation research since the 1970s. A published paper, entitled "Efficient Generation of a Biallelic Knockout in Pigs Using Zinc-Finger Nucleases," describes a general method for the generation of animals in which a chosen gene is specifically removed ("knocked out") of the pig's genome.
The lead ZFN drug in Sangamo’s pipeline is SB 509 for diabetic retinopathy. This product up-regulates the gene for vascular endothelial growth factor–A (VEGF-A). The therapeutic aims at restoring and regenerating nerves and promoting the growth of blood vessels (angiogenesis). Other products in Phase II clinical trials are SB 728 for HIV/AIDS and SB 313 for gliobalastoma. Some products in preclinical trials are designed for a variety of diseases, including hemophilia.
Sangamo aims so high that made it easy for the critics to raise skepticism. The approach is showing promise and we believe it represents genuine efforts towards developing therapeutics that induce their actions at the root-cause of diseases. In case Sangamo’s approach succeeds in stopping HIV at the door of the immune system cells, or make the sick pancreas secrete insulin again without causing known or unknown hampering side effects, these successes will make history equal to the history of the discovery of penicillin. At this stage we see a serious attempt to use the advancement in genomics to reverse diseases rather than provide symptomatic or temporary treatments that lose steam over time. This dream, which has yet to materialize has become more than ever within reach. We do not doubt that it will not take long for it to come true.
We own no shares in Sangamo and we do not intend to buy any in the next month.