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Gene Therapy for Primary Immune
Deficiency Diseases

Caroline Y. Kuo, Donald B. Kohn

Gene therapy as it is being applied for primary immune deficien- and post-transplant immune suppression; essentially, there should
cies (PIDs) represents an autologous hematopoietic stem cell be no risk of graft-versus host-disease (GvHD) from the autolo-
transplant (HSCT), in which a patient’s own stem cells are gous graft (Table 85.1). Additionally, gene therapy could have
genetically corrected and transplanted back (Fig. 85.1). Thus, increased efficacy compared to allogeneic HSCT in some condi-
gene therapy for PID builds upon decades of experience using tions, due to the potential to over-express the relevant gene
allogeneic HSCT from a healthy donor, where replacement of product (e.g. adenosine deaminase enzyme) and lead to a
some or all of a PID patient’s bone marrow hematopoietic stem supra-physiological effect from the engineered graft.
cells (HSCs) with HSC from a healthy donor can be curative of However, gene therapy may have unique risks: the potential
the disease. Although initial efforts in gene therapy were not for the genetic manipulation of the genome of the stem cells by
beneficial for the patients involved, there has been steady progress either gene addition or gene correction causing malignant
with the methods, and there is now clear-cut therapeutic efficacy transformation and leukoproliferative complications. Also, gene
using gene therapy/autologous HSCT for the three most com- therapy could have decreased efficacy if the percentage of
monly transplanted PIDs: severe combined immune deficiency transplanted stem cells that are successfully gene-corrected is
(SCID), Wiskott-Aldrich syndrome (WAS), and chronic granu- low, if the level of expression of the inserted transgene is sub-
lomatous disease (CGD)(Chapters 22, 34). Most gene therapy optimal, or if the process of ex vivo gene manipulation impairs
efforts to date have used gene addition methods in which a the stem cell’s capacity for long-term hematopoiesis. Additionally,
normal copy of the relevant gene is added to the patient’s cells, developing gene therapy for PID will require a separate research
usually using a viral vector. More recently, methods are under endeavor for each genetic etiology (e.g., ADA SCID, XSCID, Rag1
development to perform gene correction, using homologous SCID, Rag2 SCID, etc.), whereas allogeneic HSCT is a more “one
recombination (HR) DNA repair of double-stranded breaks size fits all” approach requiring less individualization for similar
induced near the site of genome mutations by site-specific classes of disorders.
endonucleases.
GENE TRANSFER TO HEMATOPOIETIC STEM CELLS
KEY CONCEPTS
For gene therapy to have an enduring effect in PID, the gene
• Some severe primary immune deficiencies (PIDs) can be treated by addition or correction must occur in the long-term pluripotent
transplantation of hematopoietic stem cells (HSCs), but this is optimal HSCs by some method that will lead to the corrective gene being
with a well-matched immune-compatible donor and may entail immune passed on to the billions of progeny blood cells made from each
complications.
• Gene therapy using autologous HSCs that have been gene-corrected HSC. Gene modification of the far more numerous, but short-
(either added or endogenously-corrected) may avoid the immune lived, progenitor cells would only lead to transient presence of
complications of allogeneic transplant and confer similar benefits. gene-corrected blood cells. The technical challenge is for the
• Stable gene addition to HSC can be done using integrating viral vectors, gene delivery to HSCs to be efficient (high percentage of the
from retrovirus and lentivirus. cells modified), to yield persistent expression, and to have minimal
• Early-phase clinical trials have been performed by applying gene therapy immediate cytotoxicity or long-term genotoxicity.
to PIDs.
• Gene therapy using gamma-retroviral vectors led to immune reconstitu- Many of the gene transfer methods used for research purposes,
tion for several forms of severe combined immune deficiency, Wiskott- such as transfection, electroporation, and nano-particle delivery
Aldrich syndrome and chronic granulomatous disease, but some patients are themselves transient, and the inserted gene would be lost by
developed leukoproliferative complications. dilution as the stem cells proliferate. Thus, most of the studies
• More recent trials using safer vectors are continuing to yield clinical to date have used viral vectors derived from the Retroviridae
efficacy with good safety profiles. family that integrate their genomes into the chromosomes of
• New techniques are being developed for precise gene editing in HSCs, the target cell to achieve persistence of the normal gene (Fig.
which may allow application to a wider spectrum of PIDs.
85.2). Genes delivered by murine gamma-retroviral, human
lentiviral (HIV), spumaviral (foamy) or alpha-retroviral vectors
The key potential advantage of autologous transplant with remain permanently covalently linked to the cellular chromosomal
gene therapy, compared to allogeneic HSCT, is that it may have DNA for stable transmission to progeny cells. The steps involved
reduced risks and a better safety profile, because it eliminates in using these types of vectors to produce a gene-modified HSC
the need for pre-transplant immune-suppressive conditioning graft are described in the Therapeutic Principles box.

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