Mor LAb | Research
Accidental (environmental or occupational) and self-inflicted (suicide) exposure to organophosphate (OP) pesticides is encountered frequently in the eme rgency room, especially in the developing world. These perennial public health i ssues are compounded by a growing concern over the potential use of OP nerve age nts such as sarin as a means of terror and nonconventional warfare. OPs disrupt neurotransmission by inhibiting synaptic acetylcholinesterase (AChE-S), leading to the accumulation of acetylcholine in the synapse and neural over-stimulation. The severity of the ensuing nicotinic and muscarinic symptoms is dose-dependent and can result in death due to cardiovascular and respiratory collapse. Those s urviving the initial insult often suffer long-term sequelae, including OP-induce d delayed neuropathy, muscle weakness, permanent brain dismorphology and social/ behavioral deficits.
OPs were first explored as insecticides, but the extr eme toxicity of OPs toward mammals prompted their development as chemical warfar e (CW) agents and the first military grade OP “nerve gases”, tabun, sarin and soman, were synthesized in Nazi Germany immediately prior to- and duri ng World War II. The cold war era saw the unfortunate spread of the technology a nd the development of yet more toxic compounds such as VX, Russian-VX and cyclos arin. In fact, CW “nerve agents” (NAs) are relatively easy to produc e, store and weaponize, and their use by terrorists and rogue governments (exemp lified by the Tokyo subway sarin attack by Aum Shinrikyo in1995) pose a major th reat to civilians and military personnel in the present global political climate .
Existing medical practices address the short-term, but not the delayed co nsequences of OP intoxication. Bioscavenging of organophosphate (OP) by human pr oteins is emerging as a promising alternative medical intervention for prophylax is and post-exposure treatment against chemical warfare nerve agents. The best-s tudied bioscavengers (BSCs) to date, meeting considerable success in pre-clinica l research, are human cholinesterases (ChEs). However, ChEs, which are highly ef ficient in binding and sequestering OPs, are also inactivated by the toxins and therefore operate as stoichiometric rather than catalytic BSCs. This necessitate s the availability of large quantities of enzymes. In the near term, outdated hu man plasma can be a first generation source of one such enzyme, butyrylcholinest erase (BChE), that may be used in clinical trials to validate its safety and eff ectiveness in biodefense. In the longer term, development of a new generation of BSCs that can catalytically degrade OPs is needed, while a cost-effective and s ustainable alternative source of BSCs must be identified to establish and mainta in a strategic reserve.
In the Mor lab, we are developing a novel means to bi omanufacture recombinant stoichiometric and catalytic BSCs based on the human pr oteins AChE, BChE and PON1 using plant-based systems.
Work is in collaboration with several laboratories at ASU and in other institutions including those of Janet Neisewander a t ASU’s Psychology Department, Hermona Soreq at Hebrew University of Jerusalem (Jerusalem, Israel), David Lenz at USMARICD, and Israel Silman and Joel Sussman at t he Weizmann Institute (Rehovot Israel). Our work is supported by the NIH (and fo rmerly by DARPA).
Containment of the HIV/AIDS pandemics depends on our ability to minimize and possibly prevent transmission of the virus. Despite the success of extensive AIDS prevention programs and powerful anti-retroviral drugs in limiting the spread of HIV in high-income countries, it is generally agreed that these efforts will have to be combined with effective prophylaxis through vaccination and the use of microbicides. These preventative efforts are even more crucial for low-income and impoverished countries, where more than 95% of people living with HIV/AIDS reside. An important consideration is that the effective vaccine should also be inexpensive to allow for its wide-spread use.
Because HIV transmission occurs most commonly through exposure of mucosal surfaces, mainly those lining the urogenital and gastrointestinal tract, to HIV-infected secretions (e.g. semen, cervico-vaginal fluid, colostrum and milk), a vaccine that would engage the mucosal immune system against a broad range of HIV subtypes is highly desirable. In addition, such immunogens can be used as a tool for the generation of poly- and monoclonal antibodies that can be used as topical microbicides which will be effective both rectally and vaginally.
In the Mor lab, we are using protein engineering for the construction of a promising vaccine-candidate consisting of a mucosal targeting component fused to a peptide corresponding to a portion of the HIV-1 envelope protein gp41, a region which is not only the target of two broad-spectrum neutralizing monoclonal antibodies, 2F5 and 4E10, but was also shown to be critical for the mucosal transmission of the virus. Systemic and mucosal antibodies raised in pre-clinical experiments against this novel immunogen were shown by us to be able to inhibit the crossing of a tight epithelial cell layer by an HIV-1 primary isolate, and were also promising in their ability to neutralize infection of CD4+ cells. The immunogen, as well as “next generation” candidates, are expressed in a variety of systems including bacteria, insect cells and plants.