Dopaminergic neuron cell therapy for treating Parkinson’s disease

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Transplanting healthy dopaminergic neuron is a new way to treat Parkinson’s disease. Bemdaneprocel (DA01) and ANPD001 are two cell therapies that are currently in clinical development for treating Parkinsons’ disease. Bemdaneprocel is an allogeneic cell therapy that uses human embryonic stem cell-derived midbrain dopaminergic neuron cells. ANPD001 is a personalized (autologous) cell therapy that uses the patient’s own skin cells to create dopaminergic neuronal precursor cells. Both Bemdaneprocel and ANPD001 have shown promising results in preclinical studies, and they are now being tested in clinical trials. 

What is Parkinson’s disease? 

Parkinson’s disease referred to as a neurodegenerative disorder. The degeneration in PD takes place in the substantia nigra region of the brain. The importance of the cells present in substantia nigra is dopamine production and secretion. These cells are called dopamine-producing cells or dopaminergic cells. 

Dopamine is a neurotransmitter. It is an essential molecule to regulate the motor function of the body. 

Degeneration in substantia nigra leads to low or no production and secretion of dopamine from the dopaminergic neurons. This results in clinical symptoms such as tremors, difficulty with balance and coordination, and stiffness. 

World Health Organization (WHO) state that 8.5 million people are affected by PD worldwide, and it is one of the major causes of disability and death. 

How cell therapy can help in Parkinson’s disease? 

Parkinson’s disease is characterized by degeneration and loss of dopaminergic neurons in the substantia nigra of the brain region. 

Presently, the cell therapy industry focuses primarily two approaches, 

1) transplanting autologous or allogenic healthy dopaminergic neuronal precursors or dopaminergic neurons

This approach focuses on 

• differentiation of dopaminergic neuronal precursors into dopaminergic neurons 
• integration into the host system
• survive long-term 
• produce dopamine 

2) transplanting autologous or allogenic healthy stem cells 

This approach focuses on 

• minimize or slow down degeneration of dopaminergic neurons 
• repair and rejuvenate pathogenic dopaminergic neurons 
• produce dopamine 

Several research groups and industries are tailoring cell therapies for PD and presenting confidence for further clinical development.

Let us explore Bemdaneprocel or BRT-DA01 and ANPD001 developments for Parkinson’s disease.

Bemdaneprocel dopaminergic neuron cell therapy for advanced parkinson’s disease

Bemdaneprocel (synonym BRT-DA01, MSK-DA-01)- a human embryonic stem cell (hESC) derived midbrain dopamine neuron cell therapy. DA01 developed by BlueRock Therapeutics, A Bayers company.

How Bemdaneprocel dopaminergic neuron cell therapy for advanced Parkinson’s disease works?

The dopaminergic neurons (dopamine progenitors or precursors) are used for transplantation (as grafting cells). As a result dopamine progenitors replace the damaged neurons. Subsequently, progenitor cells will secrete dopamine to reduce PD symptoms and improve motor functions.

Bemdaneprocel dopaminergic neuron cell therapy manufacturing and proof of concept

Human ESC working cell banks differentiated to dopamine progenitors for 16 days and cryopreserved until their use.

Key points 

• Identity, safety (sterility and mycoplasma), and viability measured during different manufacturing and batch testing intervals. In addition, cryopreserved cells analyzed for in vitro and in vivo short-term differentiation.   
• Insignificant presence of undifferentiated PSCs.
• Survival and phenotype of grafted cells measured by implanting 400000 cells unilaterally into striatum severe combined immunodeficient (SCID) /nonobese diabetic NSG mice.
  • In short, Post-three weeks of in vivo observation suggests transplanted DA01 cells do not differentiate to hypothalamic fate and are unlikely to form teratoma or neuronal rosettes in the brain. 
• 6-hydroxydopamine (6 OHDA)-induced lesions in the nude rat Parkinson’s disease model used (hemiparkinsoism). 
  • MSK-DA01 cells survived in the grafted site
  • No adverse effects caused by transplanted cells
  • Transplanted cells are able to ameliorate behavioral abnormalities. 

How patients treated with Bemdaneprocel cell therapy in Phase 1/2 clinical trial?

• Clinical trial involves two interventions 1) MSK-DA01 as biological and 2) MSK-DA01 delivery device
  • Cells were surgical transplanted into putamen region of the brain (one time)
  • Five people received 0.9 million cells per putamen, and seven got 2.7 million.
  • Patients administered immunosuppressants as it is an allogenic cell therapy. 
• Primary outcome measures involve the assessment of abnormal tissue overgrowth due to transplanted cells over a period of post 1 year transplantation.
• Secondary outcome measures include, firstly, cell survival measured by PET scan. Secondly, motor function was measured by MDS-Unified Parkinson’s Disease Rating Scale (UPDRS) motor sub-score in the “off” state,as well as changes in Waking Hours in the “Off” State. Most importantly, all were measured from baseline to 1 and 2 years post-transplant.
• Clinical trial sites conducted in:
  • United States: University of California Irvine, California; Weill Cornell medical college, New York
  • Canada: Toronto Western hospital, Toronto

Safety and Efficacy of Bemdaneprocel dopaminergic neuron cell therapy

Phase 1 study demonstrate – cell therapy is safe and well tolerated

Early evidence of cell survival and engraftment up to one year

• High Dose Cohort presented improvement in time spent in the “ON” state without troubling dyskinesia after one year i.e., 2.16 hours
  • Decrease in time spent in the “OFF” state after one year: 1.91 hours
• Low Dose Cohort presented improvement in time spent in the “ON” state without troubling dyskinesia after one year i.e., 0.72 hours
  • Decrease in time spent in the “OFF” state after one year: 0.75 hours

Impact of dopaminergic neuron cell therapy

As shown above, phase 1 study presented a meaningful outcome. Consequently, BlueRock Therapeutics expects to begin enrolling patients in Phase 2 study in first half of 2024.

ANPD001 Dopaminergic neuron precursor cell therapy

ANPD001 – a personalized (autologous) cell therapy developed by Aspen Neuroscience. It is under investigation to treat sporadic PD by replacing lost dopamine neurons.

Development of ANPD001 autologous Investigational Cell Therapy for Parkinson’s Disease

ANPD001 involves a personalized 3-step manufacturing approach.

1. Patient’s own skin cells collection
2. Reprogramming to iPSCs
3. Differentiated into dopamine neuronal precursor cells (DANPCs).

DANPCs as cell therapy product for replacement of dopamine neurons.  

The quality of the cells assessed at each manufacturing stage using artificial intelligence-based genomics tests.

Proposed Clinical trial using ANPD001 dopaminergic neuron precursor cell therapy

Phase 1/2a clinical trial of ANPD001 for patients with moderate to severe Parkinson’s disease.

DANPCs implanted via surgery to replace the patient’s lost or damaged cells.

The trial will be the first multicenter trial of an autologous iPSC-derived therapy in the U.S.

The clinical trial will evaluate the safety, tolerability, and preliminary efficacy.

Impact of ANPD001 dopaminergic neuron precursor cell therapy

Aspen Neuroscience received Fast Track Designation from the FDA for ANPD001. Above all, Aspen aims to expedite the development process. 

Author opinion

Few cell therapies, such as adult or parthenogenetic stem cells, focus on trophic and paracrine action to repair the degenerated tissues. Ultimately, concentrate on delaying Parkinson’s disease progression.

DA01 and ASP001 cell therapy products surgically implanted into the substantia nigra to replace dopamine-producing neurons. Consequently, dopamine improves circuitry and restores and regulates motor function in the striatum. 

To clarify, we are yet to learn the rebuilding of functional tissue in the presence of a few hundred thousand to a million viable and (long-term) integrated dopaminergic neurons. In addition, progressive degeneration involves engrafted cells and impacts therapeutic outcomes. Such complexities may limit the ambition of the therapeutic approach. Yet, dopaminergic neuron cell therapy is promising to improve the quality of life.

Conclusion

Dopaminergic neuron cell therapy is promising for Parkinson’s disease. However, I would like to point out that both bemdaneprocel (MSK-DA01) and ANPD001 are still clinically being developed.  Ultimately long-term safety and efficacy determine the future path.