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Implantable Biofabricated Brain Pathways

Description:

Tissue engineered nigrostriatal pathway to treat Parkinson's disease

 

Inventors

D. Kacy Cullen

Douglas H. Smith

 

Problem

Parkinson's disease (PD) affects 1-2% of people over 65 with costs estimated at $35 billion a year in the US alone (Global Data). Mitigating PD progression has been estimated to save $450,000 per patient. PD is characterized by uncontrolled tremors and issues with movement and balance. These symptoms are caused by the degeneration of a particular brain pathway connecting one part of the brain, the substantia nigra - comprised of dopaminergic neurons - to another part, the striatum. This disconnection prevents dopamine from reaching the striatum, and thereby disrupts a crucial brain circuit necessary for motor control. Current treatments for PD, such as L-DOPA and deep brain stimulation (DBS), only treat the motor symptoms but are not able to ?x the underlying cause of the de?cits: loss of the nigrostriatal pathway. 

 

Solution

To address this gap in clinical care, the ?rst “tissue engineered nigrostriatal pathway” was developed outside the body to emulate the host neural architecture. The new pathway is then precisely microinjected as a unit to “wire in” and physically replace the missing pathway. This approach  re-connects distinct brain regions restoring a crucial motor-control circuit, effectively “reversing the clock” on the neurodegenerative progression of PD. Preliminary results in animal models show success in recreating the nigrostriatal pathway which delivers the dopamine signals that are lost in PD patients.

 

Applications

• Treatment of Parkinson’s disease

• Potential treatment in several neurological and neurodegenerative diseases

• Anatomically- and physiologically-accurate in vitro test bed to better understand PD pathophysiology and establish optimal pharmacologic treatments – potentially on a patient-specific basis


Advantages

• Directly replaces brain circuitry lost to the disease, rather than only treating symptoms

• “Implantable brain pathway” for CNS repair

• Modular biofabrication protocol for building constructs with speci?c structural and functional speci?cations prior to implant

• Small form factor amenable to microinjection for minimally invasive transplant to re-establish long-distance brain pathways

• Potential use of autologous (patient-speci?c) or allogeneic (human cell line) cells as a source for dopaminergic neurons

 

Stage of Development

• Constructed the ?rst fully implantable, tissue engineered nigrostriatal pathway that emulates the form and function of the native pathway

• Bioengineered dopaminergic neurons with centimeter scale axonal projections that evoked dopamine release to functional specifications

• Completed proof-of-concept in small animals, including architecture replacement and stable synaptic integration

• Generated prototype bioengineered pathways using human stem cell derived dopaminergic neurons and axonal tracts

 

 

Bioengineered Reconstruction of the Nigrostriatal Pathway

 

 

(A) Immunocytochemical image of the axonal segment showing the robust outgrowth of dopaminergic axons in (C). The hydrogel shell is highlighted with a dotted line. (B) Image of the somatic end showing a large cluster of aggregated neurons in (C), labeled with a nuclear counterstain and antibodies for all neurons/axons. and dopaminergic neurons/neurites. (C) The cartoon (left) and actual (right) construct show the long distance axonal outgrowth. The bolus of neurons is at the bottom with axonal outgrowth projecting upwards. (D) A diffusion tensor imaging representation of the long-distance axonal tracts (lilac) that connect discrete populations of neurons in the human brain. This conceptual rendition shows the recreation of the nigrostriatal pathway (green) that degenerates in PD.

 

Desired partnerships

• License

• Co-development

• Partnership with PENN startup company

 

Intellectual Property PCT Application

WO2015066627A1

 

US non-provisional (utility) Patent Applications

15/032,677

15/534,934

 

Reference Media

Struzyna et al.,  J Tissue Eng Regen Med. (2018)

doi: 10.1002/term.2698

Cullen et al., bioRxiv (2018)

doi: 10.1101/253369

Struzyna & Adewole et al., J Vis Exp. (2017)

doi: 10.3791/55609

Harris et al., J Neurl Eng. (2016)

doi: 10.1088/1741-2560/13/1/016019

Struzyna et al., Tissue Eng Part A. (2015)

doi: 10.1089/ten.TEA.2014.0557

Download PDF

 

Docket #Z6742


Patent Information:
For Information, Contact:
Neal Lemon
Associate Director, PSOM Licensing Group
University of Pennsylvania
nlemon@upenn.edu
Inventors:
Daniel Kacy Cullen
Douglas Smith
Keywords: