Page 1198 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 85 Gene Therapy for Primary Immune Deficiency Diseases 1163

under normal physiological control. This will be essential for gene using an AAV vector to express the SERPING1 gene encoding
therapy of many PIDs, where it could be problematic if the gene the C1 inhibitor. 30
is expressed constitutively from a viral vector. For example, it was
shown that retroviral vector delivery of a normal CD40 ligand ADVANCING GENE THERAPY FOR PID FROM
gene corrected murine models of X-linked hyper-IgM syndrome EXPERIMENTAL TO STANDARD OF CARE
(XHIM), but it subsequently led to the development of lympho-
mas in the mice from constitutive rather than regulated CD40 Initial trials of gene therapy for PIDs were all performed at
29
ligand expression. Bruton tyrosine kinase (BTK), defective in tertiary-level academic medical centers, often with federal or
X-linked agammaglobulinemia, similarly may need to be expressed disease-foundation research grant funding, and they tested initial
specifically at certain stages of B-lymphocyte development for hypotheses concerning safety and efficacy. These centers may
safety and efficacy. A long list of other loci involved in PIDs continue to perform early phase clinical trials for specific dis-
may similarly be best approached by gene correction, including orders, especially where there is local expertise on the disease
SLAM, XIAP, JAK3, FOXP3, IL-10, IL7Ralpha, TACI, CTLA4, being studied. However, there is an ongoing transition to
etc. While current gene correction techniques are likely below industry-sponsored trials focused on drug product development,
the frequency of efficiency needed to yield clinical benefits for as the effective vectors and the gene-modified stem cell products
most disorders, this field is moving at a lightning pace with new they compose are advanced to licensure and marketing as
advances being reported weekly in the activity and specificity pharmaceutical agents. A common model used by these new
of a whole host of nucleases and other genome editing tools. gene therapy companies is one of central processing, at one or
a few high-grade commercial GMP facilities. The autologous
USE OF PLURIPOTENT STEM CELLS AS A SOURCE patient cells are procured at their home institution (by leuko-
OF HSC FOR GENE THERAPY OF PID pheresis or bone marrow harvest), shipped to the central process-
ing site for genetic manipulation and cryopreservation, and then
The establishment of human pluripotent stem cells (hPSCs), returned to be administered locally. Currently, gene therapy
initially as human embryonic stem cells (hESCs) and subsequently transplants have been performed at a limited number of clinical
as induced pluripotent stem cells (iPSCs), has brought the promise trial sites due to the cell processing expertise needed; presumably
of novel models to study human diseases (“disease in a dish”) under the commercial model, it may be done at any suitable
and to provide renewable sources of patient-compatible cells for hematopoietic stem cell transplant center, with the company
cellular therapies. The essentially unlimited ability to expand selling the processed cell product, like a medical device or an
hPSCs and their capacity to produce any of the cell-types in the unrelated stem cell product. Alternatively, self-contained cell
body has led to investigations to harness them for regenerative processing and manipulation devices are being developed that
medicines. In the treatment of PIDs, hPSC could provide an could allow gene modification of stem cells to be done at
ideal target to produce autologous HSCs with precise gene cor- individual institutions, without requiring highly trained staff or
rection. While techniques have been developed to perform the high-grade GMP facilities.
gene modification strategies that may be sufficiently robust for Major issues remain to be determined about cost and
clinical applications, the major roadblock is the current inability reimbursement for gene therapy. Effective gene therapy for the
to produce clinically-relevant numbers of transplantable HSCs severe diseases being approached would be expected to lead to
from hPSCs. The HSC is a relatively evanescent state and it large lifetime savings in medical costs. The one-time price can
has not been possible to “freeze” differentiation from hPSC be compared to the costs faced by the patient encumbered by
at that state, although it has been possible to proceed right the progressive nature of the underlying disease, to the costs
through the HSC stage to produce relatively pure populations for long-term protein-based therapies and possibly even to the
of individual mature blood cells. As with gene correction, the costs for allogeneic transplantation. However, those one-time
pace of scientific progress with these phenomenal cells is proceed- costs will be expensive for clinical gene therapy transplants
ing rapidly, and it is likely that new sources of gene-corrected using pharmaceutical-grade vectors and commercial-level cell
autologous HSCs will be available for clinical transplants in the processing with the attendant quality control. Thus, a single large
near future. expenditure for gene therapy may eventually be cost-effective
compared to ongoing medical costs; however, the method
GENE THERAPY FOR PID INVOLVING SERUM of financing the large up-front charge, at least in the United
PROTEIN DEFICIENCIES States with its multiple insurance companies, remains to be
determined.
Whereas many of the severe PIDs are due to blood cell defects
and thus responsive to HSCT, others result from deficiencies of CONCLUSION
serum proteins, such as complement components. Here, gene
therapy may be approached, as is being done for hemophilia, In the past decades, gene therapy for PIDs has gone from a
by direct in vivo administration of a gene-containing vector that dream for the future to a clinical reality. Gene therapy for ADA-
can permanently insert the gene into target tissues–such as the deficiency SCID has been safe and effective in most treated
liver, skeletal muscle, or endothelium–that can serve as protein patients. Although initial trials of gene therapy for XSCID, CGD
sources. In vivo gene delivery is being studied using retroviral and WAS showed efficacy, they were marred by an unacceptably
and lentiviral vectors or adeno-associated virus (AAV) vectors, high rate of complications from genotoxicity associated with
and methods for in vivo gene correction using site-specific gamma-retroviral vectors. New vectors are now in clinical trials
nucleases and homologous donor sequences are also under and are showing excellent safety profiles and higher efficacy in
development. To this end, Crystal and co-workers have recently clinical trials for ADA-deficient SCID, XSCID, WAS, and CGD
reported studies in a murine model of hereditary angioedema as well as other non-PID disorders. Approaches to direct gene