Orphan Disease Center establishes new initiative that focuses on ALS

Jan 10 2017

The Orphan Disease Center in the Perelman School of Medicine at the University of Pennsylvania has established a new Program of Excellence for Motor Neuron Disease. The new initiative will focus on ALS (amyotrophic lateral sclerosis—also known as Lou Gehrig's disease), a progressive neurodegenerative disease characterized by loss of motor neurons in the central nervous system and severe muscle weakness, with death usually occurring within five years of diagnosis. The program will pursue novel approaches, including gene therapy and genome editing to make inroads against ALS. Initial funding for these programs will be from philanthropic sources.

"I am convinced that it is time to make a serious effort to treat ALS using gene therapy," said James Wilson, MD, PhD, director of the Orphan Disease Center (ODC) and its affiliated Gene Therapy Program. "To do so, we will leverage the exciting clinical results that have been achieved in gene therapy for spinal muscular atrophy using our vectors, as well as the robust infrastructure in gene therapy translational research we have at the Orphan Disease Center and Gene Therapy Program at Penn."

About ten percent of all ALS cases are familial, implicating specific gene mutations as the cause of inherited and some acquired forms of ALS. Early studies focused on mutations in the SOD1 gene that are responsible for approximately ten percent of familial ALS, or one percent of all ALS. Genome-wide sequencing studies identified mutations in a gene called C9orf72 as a more common cause of familial ALS (40 percent) and ten percent of sporadic cases. It is unclear how mutations in genes such as SOD1 and C9orf72 cause ALS, although the presence of mutations in these genes concurrent with onset of symptoms suggests that correcting the defective protein in the motor neurons with gene therapy or genome editing may be beneficial.

The new program will build on gene-focused ALS research already taking place at the ODC. A recent advance was the discovery by the Wilson lab of second generation gene transfer vehicles -- known as vectors -- capable of shuttling genes into cells of the central nervous system. This vector has been used in multiple clinical trials including spinal muscular atrophy (SMA), an inherited disorder that leads to extreme and rapid-onset muscle weakness in infants. In its most severe form, SMA causes death within 18 months of age.

In work done by Nationwide Children's Hospital, a one-time infusion of one of the vectors discovered at Penn, expressing the normal version of the SMA gene, was associated with dramatic results in infants with SMA. Most of the children regained some motor function, and all are alive, including some who are older than three. While the genes responsible for SMA and ALS are different, they affect the same motor neurons critical for muscle function. These clinical SMA studies suggest that the technology developed in the Wilson laboratory is capable of safely and efficiently delivering genes to motor neurons, which in turn can be a mechanism for treating ALS.

The Motor Neuron Disease Program of Excellence will proceed in three phases. Initial studies will focus on gene therapy for inherited forms of ALS, beginning with patients who have defects in the C9orf72 gene. In parallel, Wilson and his colleagues will evaluate strategies based on the expression of genes encoding neuroprotective factors. This approach has the potential to benefit a larger population of patients with ALS, although it is associated with more technical risk of failure. Third, the researchers will explore the use of genome editing technologies as a more precise and durable approach to correcting mutations in genes such as C9orf72.

A group of six international experts will serve as external advisors for the program. "I am honored to serve as the chair of the advisory committee of the Program of Excellence in Motor Neuron Disease of the Orphan Disease Program at Penn," said Siddharthan Chandran, PhD, FRCP, who is chair of advisory committee and director of the Centre for Clinical Brain Sciences at the University of Edinburgh. "A greater understanding of the pathogenesis of ALS, together with advances in gene therapy that have come out of Penn, create incredible opportunities to make a difference against this devastating disease."

Source: Perelman School of Medicine at the University of Pennsylvania