The State of Fibrous Dysplasia/McCune-Albright Syndrome Research F - - PowerPoint PPT Presentation

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May 04, 2023 287 likes •454 views

The State of Fibrous Dysplasia/McCune-Albright Syndrome Research F I B R O U S D Y S P L A S I A F O U N D A T I O N ' S P A T I E N T A N D F A M I L Y C O N F E R E N C E 2 0 1 7 Michael T. Collins, MD Chief SecDon on Skeletal Disorders and

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The State of Fibrous Dysplasia/McCune-Albright Syndrome Research

F I B R O U S D Y S P L A S I A F O U N D A T I O N ' S P A T I E N T A N D F A M I L Y C O N F E R E N C E 2 0 1 7 Michael T. Collins, MD Chief SecDon on Skeletal Disorders and Mineral Homeostasis, NaDonal InsDtute of Dental and Craniofacial Research NaDonal InsDtutes of Health

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p?c canal

Skeleton

Craniofacial
Axial
Appendicular

Extra-skeleton

Endocrine
thyroid
precocious

puberty

Skin
Others

Fibrous dysplasia /McCune-Albright Syndrome

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gene protein cells ?ssue

What causes FD/MAS?

(GNAS) (Gαs)

x x

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What does Gαs do: It is a master regulator of cell ac?vity; an “on and off switch”

Skin

Café-au-lait

Ovary Bone Thyroid Pituitary

precocious puberty hyperthyroidism fibrous dysplasia growth hormone excess

Others: pancreas, heart, brain, etc.

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fat cells (adipocytes)

steoblast

cartilage cells (chondrocytes) (hematopoietic support)

The cells that make bone: skeletal stem cells, mesenchymal stem cells

steocyte

stem cell helps make blood cells bone cells

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steoblast
steocyte

stem cell

X X X

abnormal bone cells fat cells (adipocytes) (hematopoietic support) helps make blood cells

Effects of Gαs mutation in bone stem cells

cartilage cells (chondrocytes)

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GNAS, Gsα, R201

blastocyst gastrula embryo

(ectoderm, mesoderm, endoderm)

the “map” of affected ?ssues is charted in utero

skin bone endocrine

Affected tissues in FD/MAS a somatic, mosaic condition

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20 40 60 80 100 120 20 40 60 80 % Final Bone Scan Score

Chronologic Age (years)

100% of final amount of FD

(Hart, JBMR, 2007) Age disease present clinically significant disease

5.7 50% 95% 10.7 75% 99% 15.0 90% 99%

What are the effects of in utero “mapping”? Affected bones appear early

n = 109 subjects, 266 bone scans, f/u up to 32 y no new bone lesions

Affected ?ssues appear early

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Fibrous dysplasia Café-au-lait Precocious Pub. Thyroid Phosphate Growth hormone Cushing’s

5 10 15 20 30 50→

Age

Onset of manifesta?ons of affected ?ssues

sub/pre-clinical clinically evident spontaneous resolu?on possible

complete staging after age 5+ allows for determination of most affected and unaffected tissues

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0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 0.45 0.5 0-5 6-10 11-15 16-20 21-25 26-30 31-35 36-50

Fracture rate (mean # fractures/patient/year) Age (years)

(Leet, JBMR, 2004)

low phosphate normal phosphate

What are the effects of endocrine dysfunction on FD ?

Phosphate

Untreated endocrine dysfunc?on makes FD worse

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gene protein cells ?ssue The causes of FD/MAS are targets for treatment

(GNAS) (Gαs)

Oligonucleo?de therapy: small stretches of DNA/RNA the block the mutant gene Gene therapy: replace the mutant gene with a normal gene Small molecule drugs: molecules that act specifically at the mutant protein “stem cell” therapy: replace mutant cells with normal cells Cell to cell and intracellular communica?on: idenDfy and block the communicaDon system in affected cells Be_er surgical devices and techniques: beXer devices for children, comparison of techniques

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gene protein cells ?ssue

Targets for treatment & care to promote improved quality of life

pa?ents/families physicians/therapists researchers pharma support groups FDA trials

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Targets for treatment & care to promote improved quality of life

pa?ents/families physicians/therapists researchers pharma support groups FDA trials

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2 y.o. 4 y.o. 8 y.o. 11 y.o.

What FD Does What amazing people with FD Do!

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2 y.o. 4 y.o. 8 y.o. 11 y.o.

One day FD won’t do this! People with FD will be even more amazing!

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NIH Clinical Center Edmund FitzGibbon ScoX Paul Jeffrey Kim Janice Lee Clara Chen DuPont InsDtute Robert Stanton Former Trainees Elizabeth Hart Azar Khosravi Claudia Dumitrescu Penny Andreopoulou William H. Chong Tarek Metwally Jason Berglund Mary ScoX Ramnitz Diana Ovejero Beth Brillante Diala El-Maouche Alison Boyce Andrea Estrada Andrea Burke Lori Guthrie Nisan BhaXacharyya Luis Fernandez de Castro Sri Tella Pablo Florenzano Rachel Gafni Na?onal Ins?tute of Dental & Craniofacial Research Fibrous Dysplasia Founda?on Interna?onal Consor?um of FD Inves?gators (US, UK, Netherlands, France, Italy, Chile)

Thank you: to the pa?ents, families, and co-workers

Penny Feuillan Arabella Leet Paolo Bianco