Multiple System Atrophy
Multiple system atrophy (MSA) is a rare neurodegenerative disorder afflicting up to 17,000 individuals in the U.S. and an estimated 23,000 in the EU. New cases of MSA in the U.S. are estimated at 1,900 per year, and the disorder affects men and women equally. No specific genetic defect or other cause has been discovered leading to this disorder, and the cause is likely a combination of genetic tendencies and environmental factors. Clinical features of the disease typically appear between 55 and 60 years of age. MSA is a rapidly progressive condition, with 60% of those afflicted progressing from diagnosis to death within six to 10 years.
Typical signs of the disease include abnormal blood pressure variability, urinary incontinence, parkinsonism, poor balance, sleep dysfunction, incoordination of arms and legs and spasticity. The two major subtypes of MSA either display prominence of parkinsonian (MSA-P) or cerebellar (MSA-C) signs, with the former making up 60% of all afflicted individuals.
Similar to Parkinson’s disease, MSA features accumulation of intracellular α-synuclein protein. While this protein accumlates in the dopamine-producing neurons of Parkinson’s disease patients, it accumulates in MSA patients’ oligodendroglial cells that surround neurons and support their health by releasing growth factors. Recently, GDNF and dopamine levels were discovered to be markedly reduced in a brain region called the putamen, the same region that shows marked dopamine depletion in Parkinson’s disease.
Visit the National Institutes of Health Medline Plus website to learn more about MSA.
We will soon begin enrolling patients with the parkinsonian subtype of MSA (MSA-P) to assess the safety, tolerability and preliminary efficacy of GDNF gene therapy for this rapidly progressing condition. MSA is a rare neurodegenerative disorder. Because time is of the essence for these patients, we’re working to advance new treatments as quickly and safely as possible.
GDNF gene therapy for MSA
By enhancing levels of glial cell line-derived neurotrophic factor (GDNF), a naturally occurring growth factor in the brain, GDNF gene therapy is intended to promote the survival and functioning of vulnerable dopamine-producing brain cells that are “sick but not dead” in MSA-P. Taking advantage of the brain’s own cellular machinery, the proposed gene therapy provides continuous production and release of GDNF that supports dopaminergic neuronal health and may provide an advantage over intermittent protein infusions of synthetic GDNF, where brain levels may become subtherapeutic between infusions.
GDNF gene therapy consists of a delivery vector and a specific genetic payload. The vector is made up of the outer shell of the non-infectious adeno-associated virus serotype 2 (AAV2), which provides the carrying capacity and attachment properties to specific brain cell types and transfer of its genetic payload. The genetic payload carried by AAV2 includes a specific DNA sequence (gene) coding for the GDNF protein. Within target brain nerve cells, the GDNF gene induces production and local release of GDNF protein. The genetic payload also includes regulatory sequences that provide long-term stability of the transferred GDNF gene and continuous production of GDNF protein by the recipient nerve cell.
Direct brain delivery of the AAV2-GDNF therapeutic agent is performed with intraoperative MRI guidance using customized neurosurgical methods and technologies. Real-time brain MRI during surgery provides visualization of the distribution of AAV2-GDNF and allows delivery of the therapeutic agent to be tailored to each individual’s precise anatomical requirements.