Evolution and Genetic Engineering - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 720

the first procedure of gene therapy using hematopoietic stem cells as vectors to deliver genes
intended to correct hereditary diseases.
Scientists at the National Institutes of Health (NIH) (Bethesda, Maryland) have success-
fully treated metastatic melanoma in two patients using killer T cells genetically retargeted
to attack the cancer cells. This study constitutes the first demonstration that gene therapy
can be effective in treating cancer (Morgan RA, Dudley ME, Wunderlich JR, et al. “Cancer
regression in patients after transfer of genetically engineered lymphocytes”. Science 314
(5796): 126 e 129, 2006).
In March 2006, an international group of scientists announced the successful use of gene
therapy to treat two adult patients for a disease affecting myeloid cells (Ott MG, Schmidt M,
Schwarzwaelder K, “Correction of X-linked chronic granulomatous disease by gene therapy,
augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1”. Nat. Med. 12 (4):
401 e 409, 2006).
In November 2006, Preston Nix from the University of Pennsylvania School of Medicine
reported on VRX496, a gene-based immunotherapy for the treatment of human immunode-
ficiency virus (HIV) that uses a lentiviral vector for delivery of an antisense gene against the
HIVenvelope. In the phase I trial enrolling five subjects with chronic HIV infection who had
failed to respond to at least two antiretroviral regimens, a single intravenous infusion of
autologous CD4 T cells genetically modified with VRX496 were safe and well tolerated.
All patients had stable or decreased viral load; four of the five patients had stable or increased
CD4 T cell counts. In addition, all five patients had stable or increased immune response to
HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector admin-
istered in U.S. Food and Drug Administration-approved human clinical trials for any disease
(Levine BL, Humeau LM, Boyer J, et al. “Gene transfer in humans using a conditionally repli-
cating lentiviral vector”. Proc. Natl Acad. Sci. U S A 103 (46): 17372 e 17377, 2006). Data from an
ongoing phase I/II clinical trial were presented at CROI 2009.
We now turn to discussions on how to apply genetic engineering and/or genetically engi-
neered cells in bioprocesses with a focus on gene products.
1 4.6. THE PRODUCT AND PROCESS DECISION S
Genetically engineering cells can be aimed to make two major classes of products: proteins
and nonproteins. Nonprotein products can be made by metabolically engineering cells,
inserting DNA-encoding enzymes that generate new pathways or pathways with an
enhanced capacity to process the precursors to a desired metabolite. This is an area of
increasing interest because of our desire for sustainably renewable chemicals, materials,
and energy. However, most industrial emphasis traditionally has been on proteins. Tab l e
14.6 lists some of these examples. In 2011, the global market for industrial proteins is esti-
mated at $77 billion annually by RNCOS. The majority of these proteins are human therapeu-
tics, but proteins that can be used in animal husbandry, in food processing, or as industrial
catalysts are of interest. To a large extent, this has been driven by the value or price of the
product.
With therapeutic proteins that are injectable, the prime concern is the clinical efficiency of
the product. Such products must be highly pure, since strong immunogenic reactions by