ION283 for Lafora Disease

(Lafora Trial)

Overseen By Kristy Riddle, RN, BSN

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Berge Minassian

Must not be taking: Antiplatelets, Anticoagulants

Disqualifiers: HIV, Hepatitis, Renal impairment, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 24 months

10 Participants Needed

Trial Summary

What is the purpose of this trial?

This study will test the safety and efficacy of multiple doses of ION283 administered as intrathecal (IT) injections by lumbar puncture (LP). All subjects will receive ION283. The dose level of 15 mg will be studied in all subjects.

Will I have to stop taking my current medications?

The trial requires that you stop using antiplatelet or anticoagulant medications (blood thinners) like clopidogrel, warfarin, and others at least 14 days before starting the study, except for low-dose aspirin. Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

How does the drug ION283 work for Lafora Disease?

ION283 is unique because it targets the metabolism of inositol trisphosphate, which is involved in calcium release within cells. This mechanism is different from other treatments, as it focuses on altering phosphoinositide turnover, potentially addressing the neuronal degeneration seen in Lafora Disease. ^{1 2 3 4 5}

Research Team

Berge Minassian, MD

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for children aged 10-18 with genetically confirmed Lafora disease, able to walk independently and have an LDPS score ≥ 9. They must not be pregnant or breastfeeding, agree to avoid donating sperm/eggs, use effective contraception if applicable, and comply with study requirements. Exclusions include those unwilling to undergo lumbar puncture, recent drug/alcohol abuse, certain medical conditions like uncontrolled hypertension or coagulopathy, and those on specific medications.

Inclusion Criteria

I can walk 10 steps on my own and have a high level of physical disability.

I agree not to donate sperm/eggs from signing the consent until 12 weeks after the last study drug dose.

My diagnosis of Lafora disease is confirmed through genetic testing.

Exclusion Criteria

I cannot or do not want to have a lumbar puncture.

I have no major health issues found in my medical exams.

I am willing to follow the study's procedures and cooperate with the research team.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

4 weeks

Treatment

Participants receive 15 mg ION283 intrathecal bolus injection every 12 weeks

24 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ION283

Trial Overview The trial tests the safety and effectiveness of ION283 given as intrathecal injections in patients with Lafora Disease. All participants will receive a dose of 15 mg through lumbar puncture. The focus is on multiple dosing sessions to evaluate how well the treatment works over time.

Participant Groups

Group I: ION283 Arm Experimental Treatment 1 Intervention

Open label evaluation of ION283. All subjects with Lafora disease enrolled in this study will receive ION283.

Who Is Running the Clinical Trial?

Berge Minassian

Lead Sponsor

Trials

1

Recruited

10+

Elpida Therapeutics SPC

Industry Sponsor

Trials

4

Recruited

60+

Findings from Research

InsP3, when photolytically released in Purkinje neurons, can effectively induce long-term depression (LTD) similar to the activation of parallel fibers, highlighting its crucial role in synaptic plasticity.

The study found that both InsP3-induced LTD and LTD from parallel fiber activation share a common pathway, as they could not be further enhanced by each other, indicating that InsP3 receptors are essential for LTD induction in physiological conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of long-term depression and rebound potentiation by inositol trisphosphate in cerebellar Purkinje neurons. Khodakhah, K., Armstrong, CM.[2019]

Inositol 1,4,5-trisphosphate (InsP3) metabolism is significantly reduced in cerebellar tissues of patients with olivopontocerebellar atrophy (OPCA) and in Lurcher mutant mice, indicating a potential link between impaired InsP3 metabolism and neuronal degeneration.

The study found that in young Lurcher mice, InsP3 metabolism was about 40% of normal levels, and nearly absent in older Lurcher mice, suggesting that decreased InsP3 metabolism may contribute to the progression of cerebellar ataxia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inositol 1,4,5-trisphosphate metabolism in the cerebella of Lurcher mutant mice and patients with olivopontocerebellar atrophy. Vig, PJ., Subramony, SH., Currier, RD., et al.[2019]

The enzyme inositol polyphosphate 4-phosphatase, purified 3390-fold from calf brain, specifically hydrolyzes inositol 1,3,4-trisphosphate (Ins(1,3,4)P3) and inositol 3,4-bisphosphate (Ins(3,4)P2), producing inositol 1,3-bisphosphate and inositol 3-phosphate, indicating its role in inositol phosphate metabolism.

This enzyme operates optimally at a pH of 6.5 to 7.5 and is not inhibited by common ions like Li+, Ca2+, or Mg2+ at lower concentrations, suggesting a favorable safety profile for potential therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The isolation and characterization of inositol polyphosphate 4-phosphatase. Bansal, VS., Caldwell, KK., Majerus, PW.[2021]

Ins(1,3,4,6)P4 effectively releases calcium ions (Ca2+) in a dose-dependent manner, with a half-maximal effect concentration (EC50) of approximately 5.92 microM, although its maximal response is lower than that of Ins(1,4,5)P3.

In contrast, DL-Ins(1,3,4,5)P4 does not significantly influence Ins(1,4,5)P3-mediated Ca2+ release, suggesting it operates through a different receptor mechanism, highlighting the complexity of calcium signaling pathways in neuroblastoma cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interactions between inositol tris- and tetrakis-phosphates. Effects on intracellular Ca2+ mobilization in SH-SY5Y cells. Gawler, DJ., Potter, BV., Gigg, R., et al.[2019]

Injecting inositol 1,4,5-trisphosphate (InsP3) into specific neurons of Aplysia kurodai triggers an outward current that is linked to an increase in potassium conductance, indicating that InsP3 plays a crucial role in mobilizing calcium from internal stores to activate this current.

The outward current induced by InsP3 is sensitive to tetraethylammonium (TEA) and is dependent on intracellular calcium levels, suggesting that InsP3 acts as a second messenger to facilitate calcium's role in neuronal signaling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ionic mechanism of the outward current induced by intracellular injection of inositol trisphosphate into Aplysia neurons. Sawada, M., Ichinose, M., Maeno, T.[2019]

References

1. United States pubmed.ncbi.nlm.nih.gov

Induction of long-term depression and rebound potentiation by inositol trisphosphate in cerebellar Purkinje neurons. [2019]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Inositol 1,4,5-trisphosphate metabolism in the cerebella of Lurcher mutant mice and patients with olivopontocerebellar atrophy. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

The isolation and characterization of inositol polyphosphate 4-phosphatase. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Interactions between inositol tris- and tetrakis-phosphates. Effects on intracellular Ca2+ mobilization in SH-SY5Y cells. [2019]

5. United States pubmed.ncbi.nlm.nih.gov

Ionic mechanism of the outward current induced by intracellular injection of inositol trisphosphate into Aplysia neurons. [2019]