Biological Therapies for Spinal Muscular Atrophy Along the Agrin/MuSK/Lrp4/DOK7 Pathway at the Neuromuscular Junction
Background: Spinal Muscular Atrophy is a genetic disorder that results from the mutation or deletion of the SMN1 gene on chromosome 5 184.108.40.206. This disease affects infants as young as six months 2,3. This deletion leads to the loss of the protein survival motor neuron (SMN) which ultimately causes the deterioration of alpha motor neurons in the anterior horn of the spinal cord. This instrumental protein serves as a spliceosome for a wide array of proteins along the neuromuscular junction, and its loss disrupts the integral communication between neurons and muscle cells. Agrin has been discovered as one such protein that is impacted by defective splicing downstream of this genetic mutation 5. Agrin is responsible for the aggregation of acetylcholine receptors at the NMJ and binds to a receptor that consists of MuSK, Lrp4, and DOK7 5. These different receptor components are recent targets of emerging biological therapies being tested to improve the outcomes of SMA infants.
Objective: This narrative review aims at understanding the current research regarding biological agents that work along the agrin pathway in ameliorating the phenotypic and behavioral attributes of SMA mice.
Search Methods: PubMed articles from years 2017-2022 were filtered using key terms like “spinal muscular atrophy”, “agrin”, “biologics”, and “neuromuscular junction”.
Results: The most recent biologic therapy that is being administered to infants is the onasmenogene aboparvovec sold under the trade name Zolgemsma 6. This introduces a new copy of the defective or mutated gene in an attempt to increase the amount of survival motor neuron protein. Currently, more downstream therapies that operate right at the neuromuscular junction are being researched using mice. It was recently discovered that the SMN protein plays a role in the assembly of the U7 snRNP spliceosome. This complex plays an essential role in the ultimate processing of the agrin mRNA. Novel therapies are aimed at agrin and its receptor components. The first biologic agent is NT-1654 or mouse agrin. This protein improved the weight of SMA mice, decreased the amount of neurofilament at the NMJ, and improved performance on a number of behavioral exams that tested muscle strength 7. The second agent is the AAV9-DOK gene therapy that introduces a new copy of the DOK gene to improve the integrity of the agrin receptor. This improved the life span, grip strength, motor fiber area, and endplate area 8. The last agent being tested along this pathway is the MuSK agonist antibody 9. This therapy increased the full innervation of vulnerable muscle groups and improved synaptic transmission.
Conclusions: Overall, these biological agents that operate along the agrin pathway show a lot of promise in mice models. Moving these therapeutic agents forward in clinical trials and using them to augment current treatments in a combinatorial fashion shows a lot of promise in improving the outlook of spinal muscular atrophy in affected infants.
- Mercuri E, Sumner CJ, Muntoni F, Darras BT, Finkel RS. Spinal muscular atrophy. Nat Rev Dis Primers. 2022;8(1):52. Published 2022 Aug 4. doi:10.1038/s41572-022-00380-8
- Lejman J, Panuciak K, Nowicka E, Mastalerczyk A, Wojciechowska K, Lejman M. Gene Therapy in ALS and SMA: Advances, Challenges and Perspectives. International Journal of Molecular Sciences. 2023; 24(2):1130. https://doi.org/10.3390/ijms24021130
- Messina S, Sframeli M. New Treatments in Spinal Muscular Atrophy: Positive Results and New Challenges. J Clin Med. 2020;9(7):2222. Published 2020 Jul 13. doi:10.3390/jcm9072222
- Wirth B. Spinal muscular atrophy: In the challenge lies a solution. Trends in Neurosciences. 2021;44(4):306-322. doi:10.1016/j.tins.2020.11.009
- Tisdale S, Van Alstyne M, Simon CM, Mentis GZ, Pellizzoni L. SMN controls neuromuscular junction integrity through U7 snRNP. Cell Rep. 2022;40(12):111393. doi:10.1016/j.celrep.2022.111393
- Rashnonejad A, Amini Chermahini G, Gündüz C, et al. Fetal Gene Therapy Using a Single Injection of Recombinant AAV9 Rescued SMA Phenotype in Mice. Mol Ther. 2019;27(12):2123-2133. doi:10.1016/j.ymthe.2019.08.017
- Boido M, De Amicis E, Valsecchi V, et al. Increasing Agrin Function Antagonizes Muscle Atrophy and Motor Impairment in Spinal Muscular Atrophy. Front Cell Neurosci. 2018;12:17. Published 2018 Jan 30. doi:10.3389/fncel.2018.00017
- Kaifer KA, Villalón E, Smith CE, et al. AAV9-DOK7 gene therapy reduces disease severity in Smn2B/- SMA model mice. Biochem Biophys Res Commun. 2020;530(1):107-114. doi:10.1016/j.bbrc.2020.07.031
- Feng Z, Lam S, Tenn ES, et al. Activation of Muscle-Specific Kinase (MuSK) Reduces Neuromuscular Defects in the Delta7 Mouse Model of Spinal Muscular Atrophy (SMA). Int J Mol Sci. 2021;22(15):8015. Published 2021 Jul 27. doi:10.3390/ijms22158015