An open-label proof-of-concept study of intrathecal autologous bone marrow mononuclear cell transplantation in intellectual disability

Alok Sharma, Hemangi Sane, Nandini Gokulchandran, Suhasini Pai, Pooja Kulkarni, Vaishali Ganwir, Maitree Maheshwari, Ridhima Sharma, Meenakshi Raichur, Samson Nivins, Prerna Badhe, Alok Sharma, Hemangi Sane, Nandini Gokulchandran, Suhasini Pai, Pooja Kulkarni, Vaishali Ganwir, Maitree Maheshwari, Ridhima Sharma, Meenakshi Raichur, Samson Nivins, Prerna Badhe

Abstract

Background: The underlying pathophysiology in intellectual disability (ID) involves abnormalities in dendritic branching and connectivity of the neuronal network. This limits the ability of the brain to process information. Conceptually, cellular therapy through its neurorestorative and neuroregenerative properties can counteract these pathogenetic mechanisms and improve neuronal connectivity. This improved networking should exhibit as clinical efficacy in patients with ID.

Methods: To assess the safety and efficacy of cellular therapy in patients with ID, we conducted an open-label proof-of-concept study from October 2011 to December 2015. Patients were divided into two groups: intervention group (n = 29) and rehabilitation group (n = 29). The intervention group underwent cellular transplantation consisting of intrathecal administration of autologous bone marrow mononuclear cells and standard neurorehabilitation. The rehabilitation group underwent only standard neurorehabilitation. The results of the symptomatic outcomes were compared between the two groups. In the intervention group analysis, the outcome measures used were the intelligence quotient (IQ) and the Wee Functional Independence Measure (Wee-FIM). To compare the pre-intervention and post-intervention results, statistical analysis was done using Wilcoxon's matched-pairs test for Wee-FIM scores and McNemar's test for symptomatic improvements and IQ. The effect of age and severity of the disorder were assessed for their impact on the outcome of intervention. Positron emission tomography-computed tomography (PET-CT) brain scan was used as a monitoring tool to study effects of the intervention. Adverse events were monitored for the safety of cellular therapy.

Results: On symptomatic analysis, greater improvements were seen in the intervention group as compared to the rehabilitation group. In the intervention group, the symptomatic improvements, IQ and Wee-FIM were statistically significant. A significantly better outcome of the intervention was found in the paediatric age group (<18 years) and patients with milder severity of ID. Repeat PET-CT scan in three patients of the intervention group showed improved metabolism in the frontal, parietal cortex, thalamus, mesial temporal structures and cerebellum. No major adverse events were witnessed.

Conclusions: Cellular transplantation with neurorehabilitation is safe and effective for the treatment of underlying brain deficits in ID.

Trial registration: ClinicalTrials.gov NCT02245724. Registered 12 September 2014.

Keywords: Autologous bone marrow mononuclear cells; Autologous transplantation; Cellular therapy; Intellectual disability; Neurorehabilitation; Positron emission tomography-computed tomography scan; Stem cells.

Conflict of interest statement

Ethics approval and consent to participate

The Institutional Committee for Stem Cell Research and Therapy (IC-SCRT) reviewed and approved the protocol of the study. The intervention was explained to the parents in detail along with possible adverse events. Written informed consent was obtained from the parents of the patients. The consent was also video recorded.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Symptomatic improvements in patients of the intervention group with ID 6 months after cellular therapy
Fig. 2
Fig. 2
Symptomatic improvements in patients with ID who underwent only a rehabilitation regime (rehabilitation group)
Fig. 3
Fig. 3
Comparison of overall percentage improvements in the symptoms of ID between the intervention group and the rehabilitation group
Fig. 4
Fig. 4
Comparison of overall percentage improvements in ID between the intervention group and the rehabilitation group
Fig. 5
Fig. 5
Improvements in outcome measures in patients with ID in the intervention group, 6 months after cellular therapy. FIM Functional Independence Measure, IQ intelligence quotient
Fig. 6
Fig. 6
Top row: 18 F-FDG image before cellular therapy showing reduced metabolism in the prefrontal, frontal (red arrow) and cerebellum (brown arrow). Bottom row: improved 18 F-FDG metabolism after cellular therapy metabolism in the prefrontal, frontal (blue arrow) and cerebellum (pink arrow). CT computed tomography, PET positron emission tomography
Fig. 7
Fig. 7
Top row: 18 F-FDG image before cellular therapy showing reduced metabolism in the thalamus (yellow arrow), frontal lobe (orange arrow) and cerebellum (purple) arrow). Bottom row: improved 18 F-FDG metabolism after cellular therapy metabolism in the thalamus (black arrow), frontal lobe (pink arrow) and cerebellum (red arrow). CT computed tomography, PET positron emission tomography
Fig. 8
Fig. 8
Top row: 18 F-FDG image before cellular therapy showing reduced metabolism in the thalamus (red arrow) and mesial temporal structures (white arrows). Bottom row: improved 18 F-FDG metabolism after cellular therapy metabolism in the thalamus (pink arrow) and mesial temporal structures (orange arrows). CT computed tomography, PET positron emission tomography
Fig. 9
Fig. 9
Comparison of improvement in patients in the intervention group with severity of intellectual disability (ID)

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