Investigating cell therapies in animal models of Parkinson's and Huntington's disease: Current challenges and considerations

Lelos, Mariah Jillian

doi:10.1016/bs.irn.2022.09.005

Cited by 2 publications

(1 citation statement)

References 76 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The transplantation of neural stem/progenitor cells for neural repair has offered new hope for therapeutic repair of the injured spinal cord 6,25 , providing the neuronal and glial building blocks needed for tissue repair. However, despite pre-clinical success and clinical translation, limitations persist.…”

Section: [Discussion]mentioning

confidence: 99%

Human spinal interneurons repair the injured spinal cord through synaptic integration

Zholudeva,

Fortino,

Agrawal

et al. 2024

Preprint

View full text Add to dashboard Cite

Advances in cell therapy offer promise for some of the most devastating neural injuries, including spinal cord injury (SCI). Endogenous VSX2-expressing spinal V2a interneurons have been implicated as a key component in plasticity and therapeutically driven recovery post-SCI. While transplantation of generic V2a neurons may have therapeutic value, generation of human spinal V2a neurons with rostro-caudal specificity and assessment of their functional synaptic integration with the injured spinal cord has been elusive. Here, we efficiently differentiated optogenetically engineered cervical V2a spinal interneurons (SpINs) from human induced pluripotent stem cells and tested their capacity to form functional synapses with injured diaphragm motor networks in a clinically-relevant sub-acute model of cervical contusion injury. Neuroanatomical tracing and immunohistochemistry demonstrated transplant integration and synaptic connectivity with injured host tissue. Optogenetic activation of transplanted human V2a SpINs revealed functional synaptic connectivity to injured host circuits, culminating in improved diaphragm activity assessed by electromyography. Furthermore, optogenetic activation of host supraspinal pathways revealed functional innervation of transplanted cells by host neurons, which also led to enhanced diaphragm contraction indicative of a functional neuronal relay. Single cell analyses pre- and post-transplantation suggested the in vivo environment resulted in maturation of cervical SpINs that mediate the formation of neuronal relays, as well as differentiation of glial progenitors involved in repair of the damaged spinal cord. This study rigorously demonstrates feasibility of generating human cervical spinal V2a interneurons that develop functional host-transplant and transplant-host connectivity resulting in improved muscle activity post-SCI.

show abstract

Section: [Discussion]mentioning

confidence: 99%

Human spinal interneurons repair the injured spinal cord through synaptic integration

Zholudeva,

Fortino,

Agrawal

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Advancing Parkinson’s disease treatment: cell replacement therapy with neurons derived from pluripotent stem cells

Clark,

Lelos,

Loring

2024

Stem Cells

View full text Add to dashboard Cite

The motor symptoms of Parkinson’s disease (PD) are caused by the progressive loss of dopamine neurons from the substantia nigra. There are currently no treatments that can slow or reverse the neurodegeneration. To restore the lost neurons, international groups have initiated clinical trials using human embryonic or induced pluripotent stem cells (PSCs) to derive dopamine neuron precursors that are used as transplants to replace the lost neurons. Proof of principle experiments in the 1980s and 1990s showed that grafts of fetal ventral mesencephalon, which contains the precursors of the substantial nigra, could, under rare circumstances, reverse symptoms of the disease. Improvements in PSC technology and genomics have inspired researchers to design clinical trials using PSC-derived dopamine neuron precursors as cell replacement therapy for PD. We focus here on four such first-in-human clinical trials that have begun in the US, Europe, and Japan. We provide an overview of the sources of PSCs and the methods used to generate cells for transplantation. We discuss pros and cons of strategies for allogeneic, immune-matched, and autologous approaches and novel methods for overcoming rejection by the immune system. We consider challenges for safety and efficacy of the cells for durable engraftment, focusing on the genomics-based quality control methods to assure that the cells will not become cancerous. Finally, since clinical trials like these have never been undertaken before, we comment on the value of cooperation among rivals to contribute to advancements that will finally provide relief for the millions suffering from the symptoms of PD.

show abstract

Investigating cell therapies in animal models of Parkinson's and Huntington's disease: Current challenges and considerations

Cited by 2 publications

References 76 publications

Human spinal interneurons repair the injured spinal cord through synaptic integration

Human spinal interneurons repair the injured spinal cord through synaptic integration

Advancing Parkinson’s disease treatment: cell replacement therapy with neurons derived from pluripotent stem cells

Contact Info

Product

Resources

About