Preclinical Assessment of Mesenchymal-Stem-Cell-Based Therapies in Spinocerebellar Ataxia Type 3

Abstract

The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies for neurodegenerative diseases, including spinocerebellar ataxias. Spinocerebellar ataxia type 3 (SCA3)—or Machado–Joseph disease (MJD)—is the most common dominant ataxia, being mainly characterized by motor deficits; however, SCA3/MJD has a complex and heterogeneous pathophysiology, involving many CNS brain regions, contributing to the lack of effective therapies. Mesenchymal stem cells (MSCs) have been proposed as a potential therapeutic tool for CNS disorders. Beyond their differentiation potential, MSCs secrete a broad range of neuroregulatory factors that can promote relevant neuroprotective and immunomodulatory actions in different pathophysiological contexts. The objective of this work was to study the effects of (1) human MSC transplantation and (2) human MSC secretome (CM) administration on disease progression in vivo, using the CMVMJD135 mouse model of SCA3/MJD. Our results showed that a single CM administration was more beneficial than MSC transplantation—particularly in the cerebellum and basal ganglia—while no motor improvement was observed when these cell-based therapeutic approaches were applied in the spinal cord. However, the effects observed were mild and transient, suggesting that continuous or repeated administration would be needed, which should be further tested.

Genetic Ablation of Inositol 1,4,5-Trisphosphate Receptor Type 2 (IP3R2) Fails to Modify Disease Progression in a Mouse Model of Spinocerebellar Ataxia Type 3

“…Although behavioral evaluation of the IP 3 R2 KO; Q135 mice revealed the presence of several phenotypic manifestations seen in the CMVMJD135 mouse model, that gradually appear and progress during the mice lifespan, both the Q135 and IP 3 R2 KO; Q135 mice displayed equivalent balance and motor coordination deficits, loss of limb strength, and abnormal gait. Thus, the phenotypical abnormalities induced by mutant human ATXN3 were not altered by the absence of IP 3 R2, the phenotype manifested by the IP 3 R2 KO; Q135 mice which is attributable to the Q135 phenotype already well-described in the literatu [ 14 , 71 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ]. This suggests that IP 3 R2 is not a major modulator of disease severity in SCA3.…”

Intrathecal Injection of the Secretome from ALS Motor Neurons Regulated for miR-124 Expression Prevents Disease Outcomes in SOD1-G93A Mice

“…Then, the animals were injected i.p. with atipamezole hydrochloride (1 mg/mL; Antisedan ® , Pfizer, Inc., Brooklyn, NY, USA) for the reversal of the anesthesia [ 29 ]. The WT animals injected with sEVs derived from WT MNs were sacrificed at 8 h and 72 h post injection, based on our previous findings in microglia showing sEV engulfment after 24 h of incubation [ 11 ] and the results of other studies demonstrating the distribution of labelled sEVs in the SC 1 week after intrathecal injection [ 25 ].…”

“…The fore and hind paws of mice were painted with non-toxic dyes of different colours, and the mice were placed on absorbent paper in an inclined corridor so that they would walk up it since mice have the tendency to run upwards to escape [ 29 ]. We measured the stride length (in centimeters), which is the distance between the center of the fore-foot plantar and the center of the hind-foot plantar on the same side of the body, within the same stride [ 29 ]. A shorter stride length indicated abnormalities in the gait.…”

“…The mice had to remain clinging to an inverted surface of a cage lid, demonstrating their grip strength [ 29 ]. The duration (in seconds) for which the mice remained grasping the cage was measured until it reached 120 s [ 29 ].…”

“…The mice were suspended by holding their tails, and the position of their hindlimbs and toes was observed for several seconds. An abnormal phenotype is represented by the retraction of the hindlimbs toward the abdomen (clasping reflex) [ 29 ] and/or the curling of the toes (grasping reflex) during the suspension time, indicating the presence of motor dysfunctionality.…”