Editorial
Gene therapy for SCID, now up to 3!

ne
Alain Fischer, MD, PhD,a,b,c and Be
dicte Neven, MD, PhDa,d
Key words: Gene therapy
Since 2000, gene therapy has become an option to treat
severe combined immunodeficiency (SCID), a rare but lethal
condition characterized by fully defective T lymphocyte differ-
entiation caused by pathogenic variants in least 18 genes. The
current treatment by allogeneic hematopoietic stem cell trans-
plantation (HSCT) is effective but carries the risk of graft-
versus-host disease. This treatment is based on ex vivo gene
transfer by using retroviral vector (initially gammaretrovirus,
now lentivirus) to transduce the patient bone marrow CD34
cells.1,2 Stable reconstitution of T-cell counts and function
with a clear-cut clinical benefit has been achieved in the treat-
ment of X-linked SCID (gc) deficiency and adenosine deami-
nase (ADA)-SCID (Fig 1).1,2 Initial genotoxicity observed
with first-generation gammaretroviral vectors leading to onco-
gene transactivation appears to now be prevented by using
self-inactivating vectors in which an internal promoter is instead
used to drive transgene expression.1,2 Use of lentiviral vectors
as compared with gammaretrovirus-based vectors and some
conditioning regimen3,4 has led to safe, more efficient transduc-
tion and more efficient engraftment of hematopoietic cells, giv-
ing rise to differentiation of all subsets of transduced
lymphocytes (T, B, and natural killer) and long-lasting immune
reconstitution. In 2016, these advances led to the authorization
of marketing of gene therapy for ADA-SCID.2 Thus, today,
gene therapy for X-linked SCID and ADA-SCID appears to
be a safe and efficient therapeutic option. Nevertheless, it is
fair to say that meanwhile, advances in HSCT have occurred,
leading to significant improvements in success (ie, in survival
and quality of immune reconstitution).5,6
Cowan et al have now reported on the success of gene therapy
for a third SCID condition, namely, Artemis deficiency.7 This
was an awaited step because Artemis SCID (ART-SCID) raises
specific issues. The Artemis protein is part of the nonhomologous
end-joining repair machinery required for the V-D-J recombina-
tion process of antigen receptor genes in T and B lymphocytes.7
Nonhomologous end-joining is also one of the important repair
From athe Pediatric Hematology-Immunology and Rheumatology Department, H^opital
Necker-Enfants Malades, AP-HP Centre Universit
e de Paris; bthe Institut Imagine, IN-
SERM UMR 1163, Paris; cthe College de France, Paris; and dthe Universit
e Paris-Cit
e,
Imagine Institute, Laboratory of Immunogenetics of Pediatric 2, Autoimmunity,
INSERM UMR 1163, Paris.
Disclosure of potential conflict of interest: The authors declare that they have no relevant
conflicts of interest.
Received for publication January 24, 2023; revised February 9, 2023; accepted for
publication February 20, 2023.
Available online February 23, 2023.
Corresponding author: Alain Fischer, MD, PhD, Institut Imagine, 24 Boulevard Montpar-
nasse, 75015 Paris. E-mail: alain.fischer@aphp.fr.
J Allergy Clin Immunol 2023;151:1255-6.
0091-6749/$36.00
Ó 2023 American Academy of Allergy, Asthma & Immunology
https://doi.org/10.1016/j.jaci.2023.02.015
Paris, France
pathways used to fix DNA lesions. Patients with ART-SCID
are known to experience extra hematopoietic abnormalities years
after HSCT, including dental, growth, kidney, and endocrinal ab-
normalities8 that are likely enhanced by use of alkylating agents
in the conditioning regimen. Cowan et al therefore decided to
reduce the use of alkylating agents in the conditioning for gene
therapy to 25% of the classical dosage. They designed a lentiviral
vector in which the Artemis (DCLREIC) cDNA is placed under
the control of 1-kb endogenous promoter to reduce the potential
risk associated with overexpression. In all, 10 patients have been
treated, mostly at a young age thanks to early diagnosis by
newborn screening. The results are encouraging overall. No
adverse events linked to the procedure have been observed. Im-
mune reconstitution of T cells occurred in 9 of the 10 patients
(and in all 10 following a second attempt), and some patients
(n 5 4) are no longer receiving immunoglobulin replacement
therapy, with the median follow-up extending to 31 months. It
will be necessary to compare these results with those of HSCT,
notably in the long term. There is an obvious clinical benefit pro-
vided by this gene therapy approach. Transduced T and B lym-
phocytes carry a mean vector copy number (;3-5) higher than
that of transduced CD341 cells (ie, 2.5). This suggests that there
has been a selection of such cells, implying a relatively low effi-
cacy of the endogenous promoter used, nevertheless enabling
adequate regulation of Artemis protein expression. A slight
warning sign comes from the occurrence of autoimmune hemo-
lytic anemia in 4 of the patients, an event that has occasionally
been observed after gene therapy or after HSCT in patients
with SCID and is usually related to slow immune reconstitution.
The good news is that in all 4 cases the autoimmune hemolytic
anemia was transient. Nevertheless, it raises the question of the
balance between reducing conditioning to lower the risk of devel-
opment of ART-SCID–related long-term complications and
increasing the fraction of engrafted transduced stem cells. In
the future, besides potential improvement in transduction proto-
col, strategies aimed at selectively killing or displacing nontrans-
duced stem cells in vivo are of potential interest to optimize
engraftment of transduced progenitors and avoid toxicity. It is
exciting to see a third SCID disease for which 2 therapeutic op-
tions can now be considered (Fig 1). An alternative, as far as the
T-cell deficiency is concerned, might be in vitro generation and
gene correction of pro-T cells. It is likely that the same technol-
ogy will soon deliver new advances in gene therapy for SCID, at
least for RAG-1 SCID, which is a second most frequent form of
SCID.1,2 In addition, the prospect of genome editing9 based on
the CRISPR-Cas9 technology, or likely even better, on base or
prime genome editing10 of mutated SCID genes could offer addi-
tional advances in the treatment of SCID. There is even the pros-
pect that the later technologies might be used without ex vivo cell
handling. Looking back on the 55 years that have now passed
since the first success with HSCT in SCID, several bottleneck
steps have been overcome, making it possible to offer HSCT to
virtually all patients and to now consider gene therapy for at least
3 SCID conditions.
1255
1256 FISCHER AND NEVEN J ALLERGY CLIN IMMUNOL
MAY 2023

γc deficiency
IL-7/IL-15 driven expansion
2000 : γRV-GT
2009 : SIN γRV-GT
2019 : SIN LV-GT

NK NK
precursor

lymphoid
progenitors
T T
precursor

B B
precursor

HSC
ADA Artemis
deficiency deficiency
deoxynucleotides supply VDJ recombination
2002 : γRV-GT 2022 : SIN LV-GT
myeloid 2021 : SIN LV-GT
progenitors

FIG 1. Lymphopoiesis and SCID diseases corrected by gene therapy. The mechanism impaired in given
SCID diseases is shown (gray shaded boxes). gRV, Gammaretrovirus; GT, gene therapy; HSC, hematopoi-
etic stem cell; LV, lentivirus; SIN, self-inactivating vector.

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