The aim of Dr. Morgan's laboratory is to develop new and enhanced methods of viral-mediated gene transfer with specific emphasis on applications for hemophilia and HIV-1 infection.

Hemophilia directed experimentation

Hemophilia offers distinct advantages and disadvantages as a disease target for potential intervention by gene therapy techniques. On the positive side, hemophilia is potentially one of the few genetic diseases that is curable with present gene transfer technology. This is because clotting factors do not require physiological regulation, they simply need to be delivered by any cell or device to the circulation, and as little as 1% plasma concentration will likely convert a severe to a mild hemophiliac (this is associated with major positive life style change). On the negative side, current hemophilia therapies are effective and although sub-optimal, are low risk (recombinant factors have virtually eliminated viral contamination worries). Therefore, any gene therapy strategy for hemophilia should be of low risk and should likely be evaluated in the existing animal models before clinical trials. The lab's objectives and future direction with hemophilia involve a major emphasis on increasing gene expression and optimizing gene transfer efficiency.

HIV-1 directed research

In HIV-1 infection, it may be possible to apply the technology of gene therapy to deliver anti-viral agents directly to infected cells and potentially benefit the infected individual. Retroviral vectors were constructed that inhibit the HIV-1 virus at various points in the viral life cycle. The continuing goal of this work is to develop the components of the ideal anti-HIV vector. Major effort was begun in August 1996 on the implementation of our first anti-HIV gene therapy trial (in collaboration with investigators in NIAID and Transfusion Medicine/CC). This phase I/II pilot study will evaluate the safety, relative survival, and potential efficacy of infusions of activated, genetically engineered, syngeneic CD4+ T lymphocytes obtained from HIV seronegative identical twins. T cells from each seronegative twin are, transduced with a control (Neor-containing) retroviral vector and up to two additional retroviral vectors containing potentially therapeutic genes (antisense TAR and/or transdominant Rev). These engineered T cell populations are expanded 10-100 fold in culture, and then infused into the seropositive twins. The relative survival of the uniquely engineered T cell populations is monitored by vector-specific PCR, while the recipients' functional immune status is monitored by standard in vitro and in vivo testing protocols. New trials will be proposed as new vectors come on-line and may include expanded patient populations including seropositive individuals and neo-natal cord blood-based protocols.