Slide 5

Development of a canine model of SCID

Basis of immunodeficiency:

defective VDJ recombination

MSUTom BellLisa AllenCheri JohnsonBryden

StanleyAri JutkowitzTom Mullaney

Mark Bell Sarah MarshMichele Fritz

Like C.B17 SCID mice, SCID dogs have a null mutation in DNA-PKcs

Why develop a canine model of SCID?-as models of NHEJ deficiency genomic instability cancer predisposition embryonic neuronal apoptosis

-as models for bone marrow transplantation, to progress transplants for SCID children

-as substitutes for SCID mice? tumor models autoimmunity models

Immune reconstituted SCID dogs have normal lymphoid tissues with a high level of donor chimerism

Immune reconstituted dogs are immunocompetent and do not require special housing, making it feasible to actually derive a colony of SCID dogs for research.

With help of in vivo pharmacology group, and UCRFdevised protocols to maintain immunocompromised animals for extended periods.

SCID dogs are excellent hosts for human xenografts.

tested:

human ovarian carcinoma

human fibrosarcoma

rodent skin xenografts

What I would do with a large animal genome editing facility

Murine models of DNA repair deficits don't always recapitulate the human disease

DNA-PKcs

Ataxia telangiectasia (ATM kinase)

Fanconi anemia (17 different genes, FANC A-S)

Spinocerebellar ataxia with axonal neuropathy (SCAN) (TDP1)