544
Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated
with an 8–10 % mortality rate, primarily from complications of marrow-ablative
conditioning. SCD patients who happen to develop mixed chimerism after their
own bone marrow has been partially ablated, remain symptom free and have much
lower complication rate.
LentiGlobin® BB305 (Bluebird Bio) is obtained by inserting a fully functional
human βA-T87Q-globin gene into the patient’s own CD34+ HSCs by lentiviral vec-
tor encoding this gene. An open label, multi-site, single-dose, phase I study in adults
with severe SCD is evaluating the safety and effi cacy of the LentiGlobin BB305
(NCT02140554).
Hurler Syndrome
Hurler’s syndrome is the most severe form of mucopolysaccharidosis type I (MPS
IH). Children with this rare metabolic disease usually die by the age of six because
they are missing an important enzyme, alpha-L-iduronidase, which leads to progres-
sive damage in the brain, heart, bones, cartilage, liver and corneas. Patients with a
milder form of the disease, with no brain involvement, can receive enzyme replace-
ment therapy alone. However, because enzymes do not cross the blood-brain barrier,
they cannot repair the brain damage that occurs in more severe forms of the disease.
Hematopoietic cell transplantation (HCT) is a life-saving measure in MPS IH,
but a suitable hematopoietic donor is diffi cult to fi nd. Because there is no known
benefi t of immune reaction between the host and the donor cells in MPS IH, gene-
corrected autologous stem cells may be the ideal graft for HCT. A study, where
iPSCs were generated from patients with MPS IH (MPS-iPSCs), found that α-L-
iduronidase was not required for stem cell renewal, and that MPS-iPSCs showed
lysosomal storage characteristic of MPS IH and could be differentiated to both
hematopoietic and nonhematopoietic cells (Tolar et al. 2011 ). The specifi c epigen-
etic profi le associated with de-differentiation of MPS IH fi broblasts into MPS-
iPSCs was maintained when MPS-iPSCs are gene-corrected with virally delivered
α-L-iduronidase. Thus MPS-iPSCs can generate autologous hematopoietic grafts
devoid of immunologic complications of allogeneic transplantation, in addition to
generating nonhematopoietic cells with the potential to treat anatomical sites not
fully corrected with HCT.
Personalized Gene Therapy of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is the most common of the various genetic
muscular disorders. Treatment is limited to glucocorticoids that have the benefi t
of prolonging ambulation by ~2 years and preventing scoliosis. Finding a
more satisfactory treatment should focus on maintaining long-term effi cacy with a
minimal side effect profi le. Multiple treatment approaches have been tested.
16 Personalized Management of Genetic Disorders