Chorafas Foundation Award 2010 - Towne Christopher

"For the development of innovative approaches of gene therapy for the treatment of amyotrophic lateral sclerosis and other motoneuron diseases."

Adeno-associated virus-mediated gene delivery for amyotrophic lateral sclerosis and other motor neuron disorders.

THE DELIVERY OF THERAPEUTIC MOLECULES TO THE CENTRAL NERVOUS SYSTEM POSES A MAJOR CHALLENGE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES. CNS DISORDERS REQUIRE LONG-TERM INTERVENTION AND THE PRESENCE OF THE BLOOD-BRAIN BARRIER RESTRICTS THE PENETRATION OF CONVENTIONAL DRUGS TO THE DESIRED TARGET CELLS. ONE APPROACH TOWARDS STABLE DELIVERY OF THERAPEUTIC AGENTS TO THE CNS IS BASED ON THE TRANSFER OF DNA TO TARGET CELLS USING VIRAL VECTORS; A STRATEGY KNOWN AS GENE THERAPY. ALTHOUGH VIRAL VECTORS HAVE PROVIDED ENCOURAGING RESULTS IN CLINICAL TRIALS FOR DISORDERS SUCH AS PARKINSON'S DISEASE, THE SMALL DIFFUSION OF THE VECTOR FOLLOWING DIRECT INJECTION INTO THE BRAIN IS NOT APPLICABLE TO MOTOR NEURON (MN) DISORDERS THAT HAVE CELLS DISTRIBUTED ACROSS MORE THAN 50 CM OF SPINAL CORD. THE PRESENT THESIS EXPLORED NON-INVASIVE APPROACHES FOR GENE DELIVERY TO THE SPINAL CORD USING ADENO-ASSOCIATED VIRUSES (AAV). THE WORK CAPITALIZED ON THE ABILITY OF AAV TO TRAVEL ALONG THE NERVES OF MNS THAT PROJECT OUTSIDE OF THE SPINAL CORD INTO THE PERIPHERY. BY HIJACKING THIS INNATE TRANSPORT MECHANISM, THE THESIS DEMONSTRATED THAT PERIPHERAL INJECTIONS OF AAV COULD ALLOW THE VECTOR TO BYPASS THE BLOOD-BRAIN BARRIER AND EFFICIENTLY DELIVER GENES TO MNS OF THE CNS. THIS APPROACH MAY ONE DAY FACILITATE GENE THERAPY ACROSS THE SPINAL CORD FOR THE TREATMENT OF DEVASTATING MN DISEASES, SUCH AS AMYOTROPHIC LATERAL SCLEROSIS, SPINAL MUSCULAR ATROPHY AND SPINAL CORD INJURY.