Thomas
J. Sferra, M.D.
Associate Professor of Pediatrics
CMRI
Office Phone: 405-271-8001 ext 4-2375
Fax: 405-271-2281
Research
Interests:
My laboratory is involved the discovery
and development of novel gene-based therapies for genetic disorders. Our main research focus is the use of
virus-derived gene transfer vectors, particularly recombinant adeno-associated
viruses and adenoviruses, as therapeutic tools.
My recent work is focused upon two distinct classes of diseases:
lysosomal storage diseases and inflammatory bowel diseases. Each presents different challenges to the use
of gene transfer as a potential therapy.
Lysosomal
storage diseases (LSDs) are groups of inherited disorders characterized
by deficient activity of one or more lysosomal enzymes resulting in the
progressive accumulation of incompletely degraded substrates within cells. My laboratory is currently studying a subset
of the LSDs known as mucopolysaccharidoses (MPSs). These diseases are due to abnormalities in
the catabolism of glycosaminoglycans. In
general, MPSs lead to bone and joint abnormalities, enlargement of the visceral
organs, cardiovascular disease, and neurologic impairment. Current therapies, including hematopoietic
cell transplantation and enzyme replacement, do not consistently lead to
improvements in all patients, especially those with central nervous system
(CNS) involvement. To this end, we are
studying the use of gene therapy in mouse models of the MPSs. Since many patients afflicted by the MPSs are
diagnosed after the onset of symptoms and the accumulation of storage material
within the CNS, the development of therapies capable reversing preexisting
storage within the CNS is necessary. My
laboratory’s work focuses on the development of such therapies. During recent experiments we observed
significant improvements in the disease manifestations within the brain of an
MPS mouse model following the peripheral administration of an adeno-associated
virus vector during adulthood. This
novel finding is not predictable based upon previously published data, and
forms the basis of the current work in my laboratory.
Inflammatory
bowel diseases (Crohn’s disease and ulcerative colitis) are
characterized by chronic inflammation of the gastrointestinal tract. These diseases develop as a result of a
complex interaction between genetic and environmental factors leading to an
abnormal intestinal mucosal inflammatory response. The recognition that biologic agents might
have a therapeutic role in these disease led directly to the development of the
concept that IBD can be treated by gene therapy methods. The general goal of
gene therapy for IBD is to deliver genetic agents with the ability to inhibit
pro-inflammatory or enhance anti-inflammatory cytokines. The successful translation of gene therapy to
humans with IBD will require the elucidation of safe and efficient methods of
gene transfer capable of producing therapeutically relevant in vivo levels of the biologic
agents. We are investigating whether the
recombinant adeno-associated virus (rAAV) vector system is capable of achieving
these goals. We are examining two
therapeutic approaches: (i) direct gene transfer to the intestinal tract
through oral and rectal administration with the goal of local production of the
therapeutic protein, and (ii) gene transfer to the liver with the goal of
secretion into the circulation of the therapeutic protein.
This work is intimately related to the
field of glycobiology.
Muocopolysaccharidoses are diseases caused by the inappropriate
degradation and storage of unbranched polysaccharides. The analysis and quantification of these
substances is critical in the study of these diseases and the determination of
the impact of a therapeutic intervention.
In addition, the majority of lysosomal enzymes are glycoproteins. The sugar residues are essential for the
proper function and targeting of the enzymes.
Finally, for the field of gene therapy glycobiology has become an
important area of investigation since the receptors for many of the virus-based
vector systems are glycoproteins.