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WASHINGTON—At a time when the cost of developing a new drug is skyrocketing and research money is tight, it is important to be creative in designing new therapies for rare diseases and bringing them to market, according to speakers at the eighth Annual Meeting of the American Society for Experimental Neurotherapeutics (ASENT), held here in March.

This year's ASENT meeting featured a symposium on spinal muscular atrophy (SMA), an inherited motor neuron disease that is the second most common autosomal recessive disorder of children and the most common genetic cause of death in infancy, as a case study in neurology orphan drug development.

Speakers said that drug development for muscle-wasting SMA offers promise not only for those with this disease, but also possibly for patients with other diseases such as amyotrophic lateral sclerosis (ALS), muscular dystrophy, and Parkinson disease. SMA seems so ripe for effective treatment that NINDS has developed a model translational research program to accelerate therapy ( The SMA Project is a collaborative program.


“SMA is a grave and life-threatening condition, but it is the genetic disorder that is most promising for therapeutic target identification,” said Darryl C. De Vivo, MD, Sidney Carter Professor of Neurology and Pediatrics, and Co-Director of the Center for Motor Neuron Biology and Disease at Columbia University Medical Center.

Dr. De Vivo noted that babies born with the most severe form of SMA, type 1, are at risk of death before the age of two without ventilatory support. Fortunately, he said, “the unique molecular genetics of this disease lends itself to new discovery.”


The chart outlines various basic and clinical research approaches under way for spinal muscular atrophy.


Dr. De Vivo noted that advances in understanding of the genetics of SMA – which has three major phenotypes ranging from severe to mild – have fueled hope for an effective therapy. SMA is caused by a pathogenic mutation involving the SMN1 gene on chromosome 5q12.2-q13.3, said Dr. De Vivo. Humans possess another copy of the gene, called SMN2, which also creates the SMN protein. SMN1 and SMN2 are nearly identical, he said, and the only consistent difference between them is a single nucleotide variation at the start of exon 7. Almost all SMA patients have a deletion of exon 7.


Dr. Darryl C. De Vivo: “SMA is a grave and life-threatening condition, but it is the genetic disorder that is most promising for therapeutic target identification.”

The phenotypic severity of SMA is modified by the number of functioning SMN2 gene copies; an SMN2 copy number of five to eight is associated with minimal adult-onset symptoms or no symptoms at all, he said.

This observation has fueled interest in upregulating SMN2 expression any developing neuroprotectants or neurotrophic factors that could help, Dr. De Vivo said.


Dr. De Vivo noted that there is a need to define outcome measures such as muscle strength and function; pulmonary function; quality of life; and surrogate biomarkers including blood cell SMN transcripts and protein. Dr. De Vivo emphasized that in developing drugs for orphan diseases such as SMA, collaborative programs are a must, and that “strong relationships with disease advocacy foundations are absolutely key.”

High throughput screening in motor neurons is a new approach to identifying effective therapy for SMA, said Lee L. Rubin, PhD, Senior Vice President for Research and Development and Chief Scientific Officer for Curis, Inc., and former Professor of Anatomy and Developmental Biology and Director of the Eisai Institute at University College in London.

Curis has developed a procedure to produce billions of motor neurons from mouse embryonic stem cells, he said, facilitating therapy research based on genomic or proteomic analysis.

Dr. Rubin said Curis had established a screening assay for SMN levels for a molecular library, first in fibroblasts from an SMA patient. “Hits from this screen were then tested on mouse motor neurons,” he said. Unfortunately, “To date, most of the compounds that were active in the fibroblasts have been ineffective at elevating SMN levels in motor neurons,” said Dr. Rubin. “This implies that the pathways that regulate the amount of SMN vary from one cell type to another.” He added, “There may be pathways that are important in motor neurons and are simply not active in fibroblasts.” To test this hypothesis, Dr. Rubin said the next step will be to initiate a high throughput small molecule library screen in SMN-deficient motor neurons.


Katherine W. Klinger, PhD, Senior Vice President for Genetics and Genomics at the Genzyme Corporation, and Assistant Clinical Professor in the Department of Pediatrics at the University of Connecticut School of Medicine suggested that for an orphan disease it may be necessary to use multiple animal models in the preclinical research stage, because one animal model may not fully recapitulate the human disease.


A new model for translational drug discovery that can be useful in orphan disease drug development is a foundation-funded, nonprofit biotechnology company that is exclusively focused on the discovery and development of therapy for one disease, said Robert E. Pacifici, PhD, Chief Scientific Officer for CHDI, Inc., a privately held, nonprofit organization that focuses on the autosomal-dominant, neurodegenerative disorder Huntington disease (HD). “Since we have no competitors, all reagents, compounds, and protocols are shared with the broader HD research community via publicly accessible repositories,” said Dr. Pacifici, who is also an Adjunct Professor at the University of Southern California Department of Molecular Pharmacology and Chair of the NINDS SMA Project Scientific Steering Committee. “Data, information, and knowledge are disseminated via Web-based information portals in the hopes that observations made in one laboratory can be quickly leveraged in another,” he added.

The hopeful news, Dr. Pacifici said, is that “a lot of these orphan diseases are ripe for drug discovery, especially SMA and Huntington disease.”


  • ✓ SMA experts and investigators discussed the importance of collaborating with other nonprofit research and patient advocacy groups; targeted genetics research; and new clinical approaches in the pipeline.