During her residency, Cudkowicz decided to pursue clinical research centered around experimental therapeutics.[1] Since the clinical neurology program at MGH at the time was non-existent at the time, Cudkowicz explored collaborations to improve the involvement of academic clinicians in clinical trials for neurotherapeutic innovations.[1] In 1994, she established the Neurology Clinical Trial Unit at MGH.[2] The program has since become the Neurological Clinical Research Institute (NCRI).[2] She is director of the program which organizes patient data for clinical trials for neurological disorders.[2]
Cudkowicz also developed the Northeast ALS Consortium (NEALS) during her residency with a partner Jeremy Shefner in 1995.[2] The goal of NEALS is to perform collaborative and academic led clinical trials for ALS.[6] NEALS began with the involvement of 9 academic clinical centers and has since expanded to almost 100 centers worldwide.[7] Cudkowicz has since remained involved in the leadership of NEALS and is co-director of NEALS Clinical Trials Network.[8]
After her residency training, Cudkowicz became a professor at Harvard Medical School.[9] She is now Julieanne Dorn Professor of Neurology at Harvard Medical School, chief of the Neurology Service at MGH, co-director of the Neuromuscular Division at MGH, and director of the Sean M. Healey & AMG Center for ALS at MGH, which she launched in 2019.[6] Her academic research focuses on ALS, and she develops novel diagnostics and treatments for patients with ALS and organizes large clinical trials to bring new approaches closer to use in the ALS patient population.[6]
As a principal investigator in the NeuroNEXT Clinical Coordinating Center at MGH which is a part of the National Institute of Neurological Disorders and Stroke's Neurology Network of Excellence in Clinical Trials,[5] Cudkowicz is involved in leading the group to expedite therapy development for neurological disorders.[10] Through this initiative, she launched the first ALS treatment discovery pipeline, the HEALEY ALS Platform Trial, which will promote expedited research for ALS.[4]
Mutations in the superoxide dismutase 1 (SOD-1) gene were discovered to be linked to the development of ALS.[11] Cudkowicz partnered with Robert Brown, who discovered the link between SOD-1 and ALS, to develop methods to target this gene in patients with ALS.[11] Since gain of function mutations in SOD-1 are associated with ALS development, Cudkowicz and her colleagues explored the potential of silencing this gene product in patients with ALS.[12] They developed SOD-1 antisense oligonucleotides which, when given to rats, extended their survival and reversed the loss of compound muscle action.[12] Cudkowicz and her team began conducting some of the first clinical trials intrathecally administering SOD-1 antisense oligonucleotides into ALS patients with SOD1 mutations.[13]
Cudkowicz has also led clinical trials for the use of ceftriaxone, an excitatory amino acid transporter, to minimize glutamate-mediated over-excitation as a treatment for ALS.[14] Targeting over-excitability in an alternate way, Cudkowicz has been leading a trial to test the effects of Ezogabine, a potassium channel agonist, in phase II clinical trials.[15]
In 2019, Cudkowicz started to test the efficacy of autologous bone marrow-derived mesenchymal stem cells for the treatment of ALS.[16] The results have paved the way for future trials and use of intrathecal autologous bone marrow-derived mesenchymal stem cells administration.[16]
To better understand the pathogenesis of ALS, Cudkowicz explored the role of various immune cells and glial cells in disease progress and treatment.[17] She found that infusion of autologous regulatory T cells in patients with ALS slowed the progression of the disease.[17]
Cudkowicz has also explored the role of glial cells in ALS. Using PET imaging with TSPO ligands, Cudkowicz was able to deduce that glial cell activation occurs in regions associated with motor control in patients with ALS.[18] Her findings supported findings that reported activation of glial cells in neural degeneration, and confirmed their presence in brain regions associated with ALS symptoms.[18] Then, using ligand C11-PBR28, Cudkowicz, and her colleagues found further support for activation of glia correlating with severity of Upper Motor Neuron Burden, a scale used in ALS diagnosis.[19]