Tay-Sachs disease (TSD) is a rare genetic disorder arising from mutations in the gene encoding the α-subunit of β-hexosaminidase A (HexA). Hexosaminidase A is a member of a family of enzymes that are involved in the degradation of glycoconjucates including glycolipids and glycosphingolipids. These molecules are components of cell membranes and have important roles in cellular signaling processes, cell-surface recognition, cell proliferation, and neurotransmission, among other functions. HexA enzyme deficiency leads to progressive buildup of GM2 ganglioside in the central nervous system (CNS) and other tissues throughout the body. Excessive GM2 ganglioside storage in the CNS leads to neuronal death with devastating neurological and psychiatric consequences such as cognitive impairment and intellectual disability, locomotion dysfunction, seizures, and respiratory failure. Although various treatment strategies have been investigated, there are no known effective treatments for TSD other than mitigating the associated symptoms. Lack of an effective treatment results in death at the age 4-5 in the most severe form of TSD known as infantile TSD. One of the therapeutic strategies which is based on the ability of cells to take up exogenous enzyme is enzyme replacement therapy (ERT). Therefore, ERT can increase the enzyme activity in enzyme deficient cells to therapeutic levels, which is known as an effective treatment strategy for other lysosomal storage disorders (LSDs). In the present study we used HexM, a human based engineered enzyme harbouring the critical aspects of HexA enzyme, which made it a suitable candidate to improve the efficacy of ERT. To evaluate the therapeutic efficiency of a M6P-HexM and its hyperphosphorylated form; M6P-PhosHexM, we used intracerebroventricular (ICV) ERT in a TSD comparable mouse model. Assessing the biodistribution of enzymes suggested that M6P-HexM had a longer circulation time in the blood compared to M6P-PhosHexM. We also observed that after administrating the enzymes through the vein, liver enzyme activity was significantly enhanced in comparison to activity in HexA deficient animals. Brain’s enzyme activity suggested an elevation post M6P-HexM IV-infusion compared to controls. Histological analysis of brain tissue post ICV-ERT showed a reduction in the accumulated GM2 ganglioside. Delivering the enzymes directly into the cerebrospinal fluid through ICV-cannulation resulted in an increase in the ratio of GM3/GM2 ganglioside in the hippocampal region and near the implanted cannula.