The Future of Biologics and Cell-Based Therapies in Neurodegenerative and Neuropsychiatric Disease Treatment

Prepared by Salience Clinical, LLC

Independent analysis at the intersection of clinical science, regulation, and market access

About Salience Clinical

Salience Clinical, LLC is a strategic advisory firm specializing in clinical development strategy, medical affairs, regulatory alignment, and evidence generation for biotechnology, pharmaceutical, and medical technology companies. The firm focuses on complex therapeutic areas including neurology, neurodegeneration, and rare disease where scientific uncertainty, regulatory risk, and reimbursement pressure intersect.

This white paper reflects Salience Clinical’s independent, experience-driven perspective informed by senior-level engagement across clinical development, regulatory strategy, and commercialization.

Executive Summary

Cell-based therapeutics and advanced biologics represent a fundamental evolution in the treatment of neurological disease, offering mechanisms that extend beyond symptomatic management toward disease modification and, in select genetically defined conditions, potentially restorative outcomes. This white paper evaluates the current state of development, clinical evidence, manufacturing challenges, regulatory pathways, and commercial considerations shaping the adoption of these approaches across neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS), and Huntington’s disease as well as selected neuropsychiatric disorders.

Advances in induced pluripotent stem cell (iPSC)–derived neuronal replacement, gene therapy, and antibody-based biologics have moved several modalities from theoretical concepts into late-stage clinical development and regulatory approval. Key milestones include long-term safety and biological activity data from iPSC-derived dopaminergic neuron transplantation in Parkinson’s disease, FDA approvals of anti-amyloid antibodies for Alzheimer’s disease, and the transformative clinical impact of gene therapy in spinal muscular atrophy (SMA).

Despite this progress, substantial challenges remain. Consistent central nervous system (CNS) delivery, demonstration of clinically meaningful benefit in heterogeneous patient populations, scalable and reproducible manufacturing, management of immunological risk, and alignment of reimbursement models with high upfront costs all limit widespread adoption. The emergence of validated blood-based biomarkers for neurodegenerative disease diagnosis and monitoring represents a critical enabling development, improving patient selection, accelerating clinical trials, and supporting more precise therapeutic deployment.

From Salience Clinical’s perspective, success over the next decade will depend on disciplined integration of advanced therapeutics with biomarker-guided precision medicine, early and sustained regulatory alignment, and realistic economic frameworks that balance innovation with healthcare system sustainability. Organizations capable of combining scientific rigor, manufacturing excellence, regulatory sophistication, and commercial realism will define the future of neurological disease treatment.

Introduction

Traditional small-molecule and antibody-based approaches have achieved limited success in neurological diseases, with high attrition rates across clinical development. The CNS presents unique therapeutic challenges, including the blood–brain barrier, cellular heterogeneity, limited intrinsic regenerative capacity, and complex, multifactorial disease biology.

Cell-based therapies and advanced biologics offer mechanisms not achievable with conventional pharmacology alone, including neuronal replacement, sustained in situ production of therapeutic proteins, immune modulation, and structural or functional circuit support. These modalities aim to address underlying disease biology rather than exclusively mitigating downstream symptoms an objective that has long defined unmet need in neurology.

Current Landscape of Cell-Based Therapeutics

Stem Cell Approaches

Induced Pluripotent Stem Cells (iPSCs)

iPSC-derived dopaminergic neurons for Parkinson’s disease represent the most advanced neuronal replacement strategy currently in clinical development. Programs in Japan, the United States, and Europe are evaluating allogeneic iPSC-derived dopaminergic progenitors implanted into the putamen.

Follow-up data extending beyond two years from the Kyoto University program demonstrate sustained increases in putaminal dopamine uptake on PET imaging on the order of approximately 40–45% with no evidence of tumor formation or uncontrolled proliferation. These findings provide proof-of-concept that transplanted cells can survive, differentiate, and exhibit dopaminergic activity in human patients. Clinical efficacy outcomes, however, remain exploratory, and ongoing trials are designed to establish the magnitude, durability, and variability of functional benefit.

This approach utilizes HLA-matched allogeneic cells drawn from a limited haplobank, with transient immunosuppression employed during the early post-transplant period. Manufacturing strategies emphasize controlled differentiation toward midbrain dopaminergic lineages, often enriched using established developmental markers.

From a translational standpoint, manufacturing consistency, product characterization, and long-term safety surveillance represent critical success factors. Investigator-initiated trials in the United States have expanded evaluation beyond Japan, representing an important step toward broader clinical validation.

Mesenchymal Stem Cells (MSCs)

Mesenchymal stem cells exert therapeutic effects primarily through paracrine and immunomodulatory mechanisms rather than durable engraftment or neuronal replacement. Intrathecal and intranasal delivery routes are under investigation in ALS and other neurodegenerative conditions. Early-phase studies have demonstrated acceptable safety profiles, with variable and often modest efficacy signals.

MSC-derived extracellular vesicles may offer advantages in stability and manufacturability; however, consistent demonstration of clinically meaningful benefit remains limited, underscoring the importance of rigorous patient selection and endpoint strategy.

Neural Progenitor Cells

Neural progenitor cells derived from fetal tissue or pluripotent sources are being explored for stroke, traumatic brain injury, and neurodegenerative disorders. These approaches generally aim to modulate host repair mechanisms rather than reconstruct specific neural pathways, with translational success dependent on both biological effect and delivery strategy.

Biologics: Gene Therapy and Protein-Based Approaches

AAV Gene Therapy

Parkinson’s Disease

AAV-mediated delivery of enzymes, neurotransmitter-modulating proteins, or neurotrophic factors has been extensively explored in Parkinson’s disease. While early studies suggested biological activity, several randomized controlled trials failed to meet primary clinical endpoints, highlighting the challenges of placebo effects, target engagement, and disease heterogeneity.

Second-generation approaches incorporating improved vector design and MRI-guided convection-enhanced delivery are now in mid-stage development. These efforts reflect a more mature understanding of delivery as a key determinant of biological effect, though translational uncertainty remains.

Alzheimer’s Disease

Gene therapy strategies for Alzheimer’s disease focus on neurotrophic support and enhancement of pathological protein clearance. The diffuse nature of Alzheimer’s pathology poses substantial delivery and safety challenges. To date, no gene therapy approach has demonstrated clear clinical efficacy in late-stage trials, and these strategies remain investigational.

ALS and Spinal Muscular Atrophy

Onasemnogene abeparvovec (Zolgensma) demonstrated transformative benefit in SMA and established a regulatory and clinical precedent for CNS-directed gene therapy. Intrathecal approaches intended to extend applicability to older patients remain under investigation.

Efforts to translate gene therapy to ALS show promise in genetically defined subpopulations but highlight the limitations of single-target approaches in biologically heterogeneous diseases.

Antibody-Based Biologics

The approvals of lecanemab and donanemab represent the first disease-modifying therapies for Alzheimer’s disease, demonstrating statistically significant slowing of cognitive decline at the group level. These approvals mark a historic milestone while also illustrating the modest effect sizes achievable with current approaches and the importance of careful patient selection and safety monitoring.

Emerging antibody programs targeting tau, alpha-synuclein, and TDP-43 continue to refine lessons around epitope selection, brain penetration, and dosing strategy areas that Salience Clinical views as critical to next-generation success.

Neuropsychiatric Applications

Immunomodulatory biologics are under investigation for treatment-resistant depression and schizophrenia, with evidence suggesting benefit in biologically defined subgroups characterized by inflammatory signatures. These findings reinforce the broader theme of biomarker-guided precision medicine in CNS disorders.

Diagnostic Advances: Blood-Based Biomarkers

Blood-based biomarkers for Alzheimer’s disease represent a pivotal enabling development, with assays approaching the diagnostic performance of amyloid PET imaging in multiple cohorts. These tools facilitate earlier diagnosis, trial screening, and pharmacodynamic monitoring, reshaping both clinical development and clinical practice.

Manufacturing, Regulatory, and Safety Considerations

Cell and gene therapies require robust quality systems, specialized manufacturing infrastructure, and early regulatory engagement. Allogeneic approaches enable scale but introduce immunological considerations; autologous approaches introduce logistical complexity. Regulatory frameworks support innovation while emphasizing long-term safety, manufacturing consistency, and demonstration of clinical meaningfulness.

Economic and Market Considerations

High upfront costs challenge traditional reimbursement models, particularly in prevalent neurodegenerative diseases. Sustainable adoption will require robust health-economic evidence, innovative payment models, and alignment of therapeutic benefit with payer expectations.

Future Directions and Conclusion

Cell-based therapies and biologics have progressed from experimental concepts to clinical reality, though their ultimate impact will be defined by disciplined execution rather than technological promise alone. From Salience Clinical’s perspective, the next decade will favor organizations that integrate:

Biomarker-guided patient selection

Scalable, regulator-ready manufacturing

Realistic clinical endpoints

Commercial strategies aligned with payer value frameworks

The future of neurological therapeutics will be shaped not by singular breakthroughs, but by sustained, evidence-driven progress across science, regulation, and healthcare delivery.