Dr. Chris Janson and Dr. Paola Leone

Other Research-Dr. Gao

Canavan disease is a devastating degenerative disorder of the white matter caused by mutations in the aspartoacylase (ASPA) gene. Dr. Gao and his lab has a long history in Canavan disease research. In his PhD thesis work, Dr. Gao cloned, characterized the ASPA gene and genetic mutations associated with Canavan disease while at Dr. Matalon’s lab. This work laid the foundation for future therapeutic research, including gene therapy. Dr. Gao’s PhD mentor’s lab was also the first to develop a Canavan disease mouse model that, again, was a milestone in Canavan disease research. Later, during his post-doc and junior faculty years at Dr. Wilson’s Institute for Human Gene Therapy at UPenn, Dr. Gao discovered a plethora of second generation adeno-associated viruses (AAV) serotypes that are capable of crossing the blood-brain barrier (BBB) when given intravenously and thus revolutionized brain directed gene therapy and enabled scientists around the world to developed new strategies to treat genetic disorders of the brain; nowadays, AAVs are widely used in many clinical trials.

With these groundbreaking scientific contributions in mind, Dr. Gao’s lab started Canavan disease gene therapy in 2008 when he joined UMass as the founding director of the Gene Therapy Center and Vector Core.

Since then, Dr. Gao’s lab has extensively been developing AAV based gene therapy and pathomechanistic research for Canavan disease. The current 3rd generation gene therapy developed by a research team led by Dominic Gessler, a physician scientist fellow in Gao lab can completely normalize the CD knock-out mouse that dies around 28 days of age when untreated. Curiously, this 3rd generation gene therapy turns treated mice into “supermice”, outperforming healthy wild-type mice on motor function testing. In a second mouse model with a milder phenotype and almost normal survival but severe neurologic symptoms, the 3rd generation gene therapy is able to rescue even mice treated at much later adult age. Most importantly, many unpublished data suggest that the gene therapy becomes effective within weeks after treatment in mouse. So far, Gao lab has successfully treated hundreds of mice at different ages that demonstrate the efficacy of this gene therapy. Now, Dr. Gao’s lab working towards the clinical translation of this potent 3rd generation gene therapy that only requires a single intravenous injection to treat Canavan disease in mice.


 Dr. Paola Leone directs a collaborative research team that has pioneered gene therapy and drug research aimed at a cure for Canavan Disease.

We have been aggressively funding her team and lab for almost twenty years. 

 A combination of clinical and experimental expertise are essential to unlocking the secrets of Canavan disease. In addition to her core group  at  the  Cell  &  Gene  Therapy  Center  at  Rowan  University Medical School in New Jersey, key members of Dr. Leone's multidisciplinary team are located at the University of North Carolina, the University of Pennsylvania (Children's Hospital of Philadelphia), New York University and the University of Illinois. Under her direction, these neurologists and biomedical researchers are perfecting gene and drug-based therapy for Canavan and other brain diseases.

Over a decade ago, Dr. Leone and her core team spearheaded the first application of viral gene therapy to patients affected by Canavan Disease and reported long-term safety and clinical improvements in patients  treated  with  gene  therapy  (Leone  et  al.,  2012).  In  the process, Dr. Leone's team collected valuable natural history data (Janson et al., 2006) that will be used as a benchmark for future Canavan disease clinical trials.

Dr. Leone's team is currently testing the most advanced gene therapy vector in the world for Canavan disease, which was recently developed by her collaborators at UNC. Unlike all other gene therapy options, this newest gene therapy vector specifically targets the cells affected in Canavan Disease and holds a real promise for finally curing the disease.

Although extremely promising, gene therapy is only one approach to curing Canavan disease. Dr. Leone's group was among the first to propose a metabolic understanding of the disease. NAA is the main compound that is abnormally elevated in Canavan disease, and Dr. Leone's work is leading to a better understanding of the complex transport of NAA in the brains of patients with Canavan disease. In particular, Dr. Leone found that a metabolic deficit is a central feature of Canavan disease that underlies hypomyelination and cell loss (Francis et al., 2012). She also discovered that dietary therapy that fuels brain metabolism resulted in neurologic improvement and myelination  in  a  well  characterized  animal  model  on  Canavan Disease  (Francis et al ., 2014 ), and proposed a clinical study to test this treatment option. This work is leading to a better understanding of complex brain metabolism, with direct applications to Canavan disease as well as a broader significance for other brain diseases including Alzheimer's and brain cancer.

In terms of drug therapy, Dr. Leone and collaborators discovered the neurologic benefit of lithium citrate administration in Canavan patients (Assadi et al., 2010), which is currently one treatment option to help preserve  brain  function  in  newly  diagnosed  Canavan  patients. Building upon this initial success, her collaborator Dr. Janson at the University of Illinois is developing new cell-based drug screening assays which hopefully will lead to more pharmaceutical options for Canavan and related conditions.
Finally, in work co-funded by the NIH and Canavan Research Illinois and partners in biotechnology, Dr. Leone is testing the benefit of human neural stem cell therapy, already approved for clinical use, in preclinical models.

While actively engaged in novel preclinical developments for a cure, Dr. Leone's team continues to assist with the management and care of Canavan patients worldwide and provides knowledgeable support on clinical care and genetic screening of rare mutations.