Page 525 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 35 Primary T-Cell Immunodeficiencies 505

and deregulated expression of oncogenes. Use of a γ-retrovirus lymphoma, have also been reported recently as sole manifestations
vector in patients with Wiskott-Aldrich syndrome resulted in of T-cell immunodeficiencies. With the increased recognition of
partial or complete resolution of immunodeficiency, however 7 genetic aberrations linked to these diseases, we are likely to see
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of the 10 patients receiving gene therapy developed malignancy. a great expansion of novel phenotypes associated with known
Furthermore, in patients with chronic granulomatous disease, genotypes, although not necessarily with identical mutations.
long term immune reconstitution was variable and myelodys-
plastic syndrome was reported in 3 of 10 patients. Between 1999 ON THE HOrIZON
and 2006, trials for IL2RG deficiency initially reported successful
immune reconstitution in 18 of 20 recipients; however clonal • Whole exome sequencing can be technically performed using DNA
derived from a dried blood spot. Implementing this technology to
proliferation caused by insertional mutagenesis occurred in 5 newborn screening will immensely improve the outcome of patients.
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recipients after 2 to 5 years. Taken together, these results • In the future, closer attention will be paid to family members of patients
prompted a discontinuation of these trials, and a call to develop with overt immunodeficiency to better understand the clinical impact
novel and much safer vector constructs, including self-inactivating of monoallelic/carrier genetic aberrations.
γ-retrovirus and lentiviral vectors. To date, follow-up studies in • Whole exome sequencing is widely reported to be successful in only
patients with IL2RG deficiency utilizing a self-inactivating 40% of cases. Whole-genome sequencing and development of new
bioinformatics algorithms would likely yield better results.
γ-retrovirus vector have so far been encouraging, with reports • Although hematopoietic stem cell transplantation can cure patients
of excellent immune reconstitution and no evidence of insertional with T-cell deficiency, in many cases, it remains a high-risk procedure
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mutagenesis. In an ongoing study, the application of lentiviral and may not be optimal therapy for a growing number of newly defined
vectors in Wiskott-Aldrich syndrome have demonstrated multi- combined immunodeficiencies. New developments in gene therapy
lineage engraftment of corrected cells, both in the bone marrow and gene editing are likely to expand as alternative treatments.
and peripheral blood, with no reports of clonal expansion or
leukemia. This expansion in diagnosis of profound T-cell deficiencies
With the advancement in technology and progress made in raises new opportunities to study mechanisms underlying
vector design, gene therapy is a viable option for challenging autoimmunity as well as lymphoid malignancies. However, these
forms of primary immunodeficiency, in which current available cases may pose new challenges, such as choice of HSC therapy.
treatments are insufficient. Further prospective trials should help to determine the validity
of transplantation compared with conservative immunosuppres-
Gene Editing sive therapy or innovative new biological treatments.
Gene editing technologies allow precise correction of the defective With challenges come opportunities, and we are living in an
genomic DNA site and are thus a promising alternative to HSCT exciting era of improved tools to enhance the understanding
(Chapter 85). Using engineered endonucleases, such CRISPR/ of the molecular changes and mechanisms leading to profound
Cas9, zinc finger nucleases, and transcription activator-like T-cell deficiency and associated autoimmunity and malignancy.
effector nucleases, double-stranded breaks are introduced into This wealth of knowledge should help advance novel treatments.
specific sequences of the genomic DNA and repaired through
homology-directed repair. In the presence of a DNA repair Please check your eBook at https://expertconsult.inkling.com/
template containing a functional version of the defective gene, for self-assessment questions. See inside cover for registration
the double-stranded break is accurately repaired with the cor- details.
rected sequence incorporated. While gene editing provides greater
control over site integration than retrovirus-based gene therapy, REFERENCES
the technique is still in the pre-clinical phase, with developments
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