Manfredsson Laboratory

Laboratory Focus

The Manfredsson Laboratory has three main areas of focus.

First, we are developing novel gene therapy modalities for neurological disorders. The use of viruses to deliver therapeutics in disease has enjoyed great success over the last few years; however, significant barriers remain. We are addressing these barriers by using the latest genetic and bioinformatic tools to engineer novel viral vectors with enhanced efficiency and specificity for cells in the central nervous system (CNS) and engineering novel payloads to modulate cells in various ways.

Spinal cord transduction following subpial AAV delivery.

We are also using gene therapy to study, model, and treat neurodegenerative disorders, with a primary focus on Parkinson’s disease, but also including studies involving ALS, Alzheimer’s disease, and Huntington’s disease.

Finally, Dr. Manfredsson also guides the synucleinopathy brain bank, which aims to build a repository of brain tissue derived from patients with Parkinson’s disease, multiple system atrophy, or dementia with Lewy bodies.

Normalization of Calcium Transients in Parkinson’s Disease (PD)

A large body of data has shown that calcium transients (facilitated via the L-type voltage-gated alpha 1D channel- Ca_V1.3) are dysregulated in Parkinson’s disease. In the striatum, this leads to maladaptive plasticity and the debilitating side-effect: levodopa-induced dyskinesia (LID). The activity in nigral dopamine neurons (the cells that die in PD) is a likely contributor to the vulnerability of these cells in disease.

Because this channel is present in most tissues throughout the body, it cannot be manipulated with small molecules. It is, therefore, a perfect target for gene therapy. In an array of studies in rodents and nonhuman primates, we have shown that reducing the levels of this channel in specific areas of the brain prevents LID and even reverses disease symptoms. Ongoing studies are now evaluating the potential for this approach to halt disease. Moreover, we are currently undertaking IND-enabling studies to translate this exciting approach into the clinic.

Defining the Mechanisms Underlying Nonmotor Symptoms in Parkinson’s Disease

It is a little-known fact that nearly all PD patients can suffer from a wealth of nonmotor problems, ranging from anxiety, impulse control, and cognitive decline, among many others. To this end, we have focused our studies on circuits outside the nigrostriatal neurons that change with disease. For instance, dorsal raphe 5-HT neurons.

These neurons progressively degenerate in disease. However, surviving cells adopt what we refer to as maladaptive plasticity—changing their synaptic connections in brain areas that drive symptoms such as anxiety. Using a combination of genetic techniques (DREADD, optogenetics), single-cell synaptic mapping in animals and humans, electrophysiology, and behavior, we are working to define these changes and how they may contribute to disease symptoms.

Defining the Role of Alpha-Synuclein (α-syn) in Parkinson’s Disease and the Normal Brain

The protein α-syn has been linked to PD; it is mutated in familial forms of PD, and it is present in proteinaceous aggregates (Lewy bodies) in sporadic disease. Because α-syn has a high propensity to aggregate, it is broadly assumed that its role in disease is that of a toxic gain-of-function. However, we have shown that acute removal of α-syn protein can also damage neurons, suggesting that disease can result from this protein’s loss of function.

This begs the question: What is the crucial physiological function of α-syn? Using a variety of approaches, such as omics, electrophysiology, and high-content analyses, we aim to define the functional properties of this protein and whether retaining these functions can prevent neurons from dying.

Guided Evolution of Adeno-Associated Viruses for Brain Immune Cells

It is increasingly recognized that immune cell activity and inflammation are key components of neurodegenerative disease. Unfortunately, cells modulating CNS inflammation, such as microglia, are not readily infected with adeno-associated virus (AAV).

glial transduction — Glial transduction.

To that end, we are currently evaluating an AAV library that was engineered by incorporating small stretches of known glial ligands into the virus’s capsid. Using a variety of positive and negative selection techniques, we are now identifying candidates from this library that exhibit a unique tropism for different subsets of brain glia.