D-Cycloserine for Serine Palmitoyltransferase Inhibition

D-Cycloserine for Serine Palmitoyltransferase Inhibition: Treatment of a Single Patient With a Complex Hereditary Spastic Paraplegia Due to a De Novo Variant in the SPTSSA Gene

The overarching objective of this study is to mitigate the neurological decline associated with SPTSSA related Complex Hereditary Spastic Paraplegia

Study Overview

• Status: Completed
• Conditions: Hereditary Spastic Paraplegia
• Intervention / Treatment: Drug: D-cycloserine

Detailed Description

At each visit a medication reconciliation will be performed which will include medications, vitamins, herbal preparations, and supplements. For each medication the investigators will record start and end dates of administration, dosage, frequency, and reason for use. After the initial medication reconciliation the investigators will review the participant's medications with pharmacy to determine if any significant drug-drug interactions exist between the participant's medications and D-Cycloserine. If such interactions are discovered the investigators will collaborate with the participant's prescribing physician to determine if dose alterations/discontinuation would benefit the participant while receiving D-Cycloserine therapy. For subsequent medication reconciliations at follow up visits the investigators will do the same for any new medications that the participant may be taking.

After clinical assessments, the investigators will routinely return results to the participant by phone or by secure messaging in the EMR (per standard clinical protocol).

In addition to the scheduled study visits the participant is encouraged to follow up with the the investigators via phone or by secure messaging in the EMR should they have any questions or updates about interval changes in the participant's clinical status. Each report will be assessed by the investigators and based on their clinical judgement the participant may require additional follow up evaluations.

If the results are acceptable and there is no contraindication to treatment the investigators will begin dosing D-Cycloserine following the baseline visit.

The D-Cycloserine (250 mg) capsules will be compounded to a suspension of 25 mg/mL, and for a starting dose the participant would take 15 mg/kg (253 mg = 10.1 mL) by mouth once daily. Throughout the study, based on serial clinical evaluations, sphingolipid levels, and toxicity monitoring the investigators will adjust the dose between 15-20 mg/kg/day at the discretion of the Principle Investigator (PI). The PI reserves the right to stop, temporarily hold, or adjust the dose of the medication at their discretion. As the participant grows and gains weight the investigators will adjust the dose as necessary in order to keep it at the goal of 15 to 20 mg/kg/day.

The time to peak concentration for D-cycloserine is 4 to 8 hours with a half-life elimination (with normal renal function) of 12 hours. Studies in pediatric patients recommend targeting serum concentrations of 25 to 30 mcg/mL to minimize neurotoxicity. Therefore ~6 hours after initial administration the investigators would draw a D-Cycloserine level to best understand the peak concentration obtained in the participant.

Given that concomitant pyridoxine is recommended to prevent cycloserine-induced neuropathy, at the time of D-Cycloserine initiation the investigators would also plan to supplement with pyridoxine. The pyridoxine (50 mg) tablets will be compounded to a suspension of 50 mg/mL, and the participant will take 0.4 mL (20 mg = approximately 1.18 mg/kg) by mouth once daily. If there is ongoing concern for drug related neuropathy at this starting dose then pyridoxine dose adjustments can be made towards a max of 2 mg/kg/day.

The schedule of assessments will be followed as long as the participant tolerates the treatment and continues to do well clinically. If there are concerns for tolerability, adverse events, or serious adverse events, at their discretion the PI reserves the right to stop, temporarily hold, or adjust the dose of the medication as well as increase the frequency of follow up assessments.

Weekly assessments will be conducted by the investigators to assess outcomes measures for the four weeks following the baseline visit. Following this period, outcome measures will be assessed every two weeks for a period of 8 weeks. Afterwards, pending reassuring data and lack of contraindications the investigators will space out assessments to once a month. At the 6 month interval assessment, a repeat MRI and Lumbar Puncture will be performed. Visits will continue monthly until 1 year post-baseline. A final MRI and Lumbar Puncture will be performed at the 1 year interval visit.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• • Informed consent provided by the participant's parents.

  • Ability to travel to the study and assessment sites (Massachusetts General Hospital Main Campus, 55 Fruit St, Boston, MA 02114 and MGH IHP Impact Practice Center, 2 Constitution Wharf, Charlestown, MA 02129) and adhere to study-related follow-up examinations and/or procedures and provide access to participant's medical records.
  • Clinical phenotype, neuroimaging, genetic testing and biochemical results consistent with a diagnosis of SPTSSA-related Complex Hereditary Spastic Paraplegia

Exclusion Criteria:

• • Participant has any known contraindication to or unwillingness to undergo procedures listed in the protocol

  • Use of investigational medication within 5 half-lives of the drug at enrollment
  • Participant has any condition that, in the opinion of the Site Investigator, would ultimately prevent the completion of study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: D-Cycloserine; D-Cycloserine Administered for Complex Hereditary Spastic Paraplegia	Drug: D-cycloserine; Pyridoxine also prescribed to help prevent neurologic adverse events related to D-Cycloserine.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of treatment related serious adverse event	Frequency of treatment related serious adverse events as assessed by CTCAE Version 5.0	From baseline to the end of treatment at 1 year
Concentration of D-Cycloserine	Concentration of D-Cycloserine in mcg/mL from serum blood samples drawn 6 hours after dosing	From baseline to the end of treatment at 1 year
Increases in serum AST and ALT in (U/L)		From baseline to the end of treatment at 1 year
Presence or Absence of Changes in Brain Magnetic Resonance Imaging	Changes in Brain Magnetic Resonance Imaging associated with adverse events	From baseline to the end of treatment at 1 year
Presence or Absence of Changes in Spine Magnetic Resonance Imaging	Change in Spine Magnetic Resonance Imaging associated with adverse events	From baseline to the end of treatment at 1 year
Presence or Absence of Changes in Electroencephalogram (EEG)	Changes in Electroencephalogram (EEG) associated with adverse events	From baseline to the end of treatment at 1 year
Presence or Absence of Changes on audiogram.	Changes in audiogram associated with adverse events related to hearing loss	From baseline to the end of treatment at 1 year
Presence of Absence of Changes in nerve conduction studies.	Changes in nerve conduction studies related to adverse events	From baseline to the end of treatment at 1 year
Presence or Absence of Changes in cognitive profile on neuropsychological testing.	Changes in neuropsychological testing related to adverse events	From baseline to the end of treatment at 1 year
Changes in gross motor function as measured by the Gross Motor Function Measure (GMFM-88)	Higher scores indicate better capacity for gross motor function	From baseline to the end of treatment at 1 year
Changes in spasticity as measured by findings on the Tardieu Spasticity Scale	That Tardieu Spasticity Scale is scored from 0 to 5. Lower scores are given for less spasticity while higher scores are given for more spasticity	From baseline to the end of treatment at 1 year
Changes in performance as measured by scores on Pediatric Evaluation of Disability Inventory Computer Adaptive Test (PEDI-CAT)		From baseline to the end of treatment at 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Decrease in sphingolipid levels	Decrease in sphingolipid levels in blood and CSF, targeted to be maintained at ~50% of pre-treatment levels	From baseline to the end of treatment at 1 year
Decrease in serum neurofilament light chain level	Decrease in serum neurofilament light chain level (pg/mL), targeted to be maintained at ~50% of pre-treatment levels	From baseline to the end of treatment at 1 year

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital
• Collaborators: National Institute of General Medical Sciences (NIGMS); Uniformed Services University of the Health Sciences

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2024
• Primary Completion (Actual): March 17, 2026
• Study Completion (Actual): March 17, 2026

Study Registration Dates

• First Submitted: March 4, 2026
• First Submitted That Met QC Criteria: April 17, 2026
• First Posted (Actual): April 21, 2026

Study Record Updates

• Last Update Posted (Actual): April 21, 2026
• Last Update Submitted That Met QC Criteria: April 17, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: D-Cycloserine; SPTSSA Gene; Complex Hereditary Spastic Paraplegia
• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Genetic Diseases, Inborn; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Congenital Abnormalities; Heredodegenerative Disorders, Nervous System; Nervous System Malformations; Polyneuropathies; Hereditary Sensory and Motor Neuropathy; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Spastic Paraplegia, Hereditary; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Amino Acids; Oxazolidinones; Oxazoles; Isoxazoles; Serine; Amino Acids, Neutral; Cycloserine
• Other Study ID Numbers: 2024P001068; 5T32GM007748-47 (U.S. NIH Grant/Contract); GR0235874 (Other Grant/Funding Number: The Avery Project)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: This is a single participant study. All IPD that underlie results in a publication will be shared
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No