The Long Journey from Diagnosis to Therapy

I was honored to be asked by the Editorial Committee of the Annual Review of Genomics and Genetics to write an autobiographical account of my life in science and in genetics in particular. The field has moved from mapping Mendelian disorders 40 years ago to the delivery of effective therapies for some monogenic disorders today. My 40-year journey from diagnosis to therapy for Duchenne muscular dystrophy has depended on collaborations among basic scientists, clinicians, medical charities, genetic counselors, biotech companies, and affected families. The future of human genetics looks even more exciting, with techniques such as single-cell sequencing and somatic cell CRISPR editing opening up opportunities for precision medicine and accelerating progress.

Download Full-text

CRISPR Correction of Duchenne Muscular Dystrophy

Annual Review of Medicine ◽

10.1146/annurev-med-081117-010451 ◽

2019 ◽

Vol 70 (1) ◽

pp. 239-255 ◽

Cited By ~ 41

Author(s):

Yi-Li Min ◽

Rhonda Bassel-Duby ◽

Eric N. Olson

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Recent Progress ◽

Scaffolding Protein ◽

Genetic Mutations ◽

Striated Muscles ◽

Gene Encoding ◽

Monogenic Disorders ◽

The Third ◽

Dystrophin Expression

The ability to efficiently modify the genome using CRISPR technology has rapidly revolutionized biology and genetics and will soon transform medicine. Duchenne muscular dystrophy (DMD) represents one of the first monogenic disorders that has been investigated with respect to CRISPR-mediated correction of causal genetic mutations. DMD results from mutations in the gene encoding dystrophin, a scaffolding protein that maintains the integrity of striated muscles. Thousands of different dystrophin mutations have been identified in DMD patients, who suffer from a loss of ambulation followed by respiratory insufficiency, heart failure, and death by the third decade of life. Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD. Here, we review recent progress toward the development of possible CRISPR therapies for DMD and highlight opportunities and potential obstacles in attaining this goal.

Download Full-text

Human Genetics of Pain

The Oxford Handbook of the Neurobiology of Pain ◽

10.1093/oxfordhb/9780190860509.013.1 ◽

2019 ◽

pp. 100-127 ◽

Cited By ~ 1

Author(s):

James J. Cox ◽

Ingo Kurth ◽

C. Geoffrey Woods

Keyword(s):

Normal Development ◽

Human Genetics ◽

Single Gene ◽

Gene Mutations ◽

Sequencing Technology ◽

Nociceptive Neurons ◽

Analgesic Drugs ◽

Monogenic Disorders ◽

Mendelian Disorders ◽

Cellular Pathology

Inherited pain disorders are typically rare in the general population. However, in the postgenomic era, single-gene mutations for numerous human Mendelian pain disorders have been described owing to advances in sequencing technology and improvements in pain phenotyping. This article describes the history, phenotype, gene mutations, and molecular/cellular pathology of painless and painful inherited monogenic disorders. The study of these disorders has led to the identification of key genes that are needed for the normal development or function of nociceptive neurons. Genes that are covered include ATL1, ATL3, DNMT1, DST, ELP1, FLVCR1, KIF1A, NGF, NTRK1, PRDM12, RETREG1, SCN9A, SCN10A, SCN11A, SPTLC1, SPTLC2, TRPA1, WNK1, and ZFHX2. The study of some Mendelian disorders of pain sensing has the potential to lead to new classes of analgesic drugs.

Download Full-text