1: Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

J Clin Invest.

2023 Jun 15;133(12):e165908. doi: 10.1172/JCI165908.

Keigo Takahashi, Elizabeth M. Eultgen, Sophie H. Wang, Nicholas R. Rensing, Hemanth R. Nelvagal, Joshua T. Dearborn, Olivier Danos, Nicholas Buss, Mark S. Sands, Michael Wong, and Jonathan D. Cooper

Neuronal ceroid lipofuscinoses (NCL) are a group of hereditary neurodegenerative diseases caused by deficiencies in multiple lysosomal proteins. Type 2 NCL (CLN2) is caused by a deficiency of the proteolytic enzyme TPP1. Patients develop epilepsy between the ages of 2 and 4, followed by progressive regression, ataxia, and vision loss, leading to death by their teens. Much of the pathophysiology of this disease remains unknown. Currently, the only approved treatment is intracerebroventricular enzyme replacement therapy, which requires biweekly administration, and there is a demand for the development of more effective and long-lasting treatments. We conducted behavioral and neuropathological analyses of Cln2 knock-in mice carrying a pathogenic mutation common in patients. We found that the mice develop lethal epileptic seizures, which are preceded by a decrease in GABAergic neurons in the cerebral cortex. Furthermore, we demonstrated that gene therapy using adeno-associated virus serotype 9 (AAV9) ameliorates these epileptic seizures and neuropathological abnormalities, and significantly extends the survival period. Preparations are currently underway for a clinical trial of this gene therapy.

(Keigo Takahashi, Class of '94, Washington University in St. Louis)

Annals of the Rheumatic Diseases.

2023; 82(8). doi: 10.1136/ard-2022-223759

Takeuchi T, Tanaka S, Murata M, Tanaka Y.

Although the treatment of rheumatoid arthritis (RA) has made relative progress with the introduction of molecularly targeted therapeutic agents such as biologic agents and JAK inhibitors, there remains a high level of unmet need in clinical practice. One new target molecule is Bruton's tyrosine kinase (BTK). It is expressed in B cells, macrophages, mast cells, platelets, and osteoclasts, and is involved in their intracellular signal transduction. TAS5315 is a BTK inhibitor developed in Japan. It is a covalent drug that forms a covalent bond with a specific amino acid residue of the target protein, irreversibly inhibiting its function, and shows high specificity for osteoclasts. The results of the first-ever early phase II trial to verify the efficacy of this drug for rheumatoid arthritis have been published (Figure). In Part A, a three-arm randomized controlled trial (n=91) was conducted with a placebo group and two active drug dose groups. In the subsequent Part B, the placebo group was switched to the active drug, and the trial continued for 24 weeks (36 weeks from the start of the trial) (n=84). With the participation of Professor Mitsuru Murata of Laboratory Medicine, the bleeding risk was carefully evaluated. The primary endpoint, the ACR20 response rate, was high in the active drug group at 78.9%, but the placebo group also had a high rate of 60%, resulting in a P-value of 0.053, which was unfortunately not statistically significant. However, it showed promising results in other clinical effects, such as the suppression of autoantibody production and the inhibition of joint destruction. Regarding safety, bleeding symptoms such as subcutaneous hemorrhage, petechiae, and purpura were observed in nine cases. However, with the exception of one serious adverse event of cerebellar hemorrhage, the symptoms resolved with continuation or discontinuation of the drug. It is hoped that its efficacy will be verified in further clinical trials.

(Tsutomu Takeuchi, Class of '59, President, Saitama Medical University,

Mitsuru Murata, Class of '60, Professor, Center for Clinical Medical Sciences, International University of Health and Welfare)

Nature Reviews Clinical Oncology.

2023;20(7):453-469. doi: 10.1038/s41571-023-00767-w

Hirata Y, Noorani A, Song SM, Wang LH, Ajani JA.