An overview of the ongoing trials and fresh knowledge that medicine has acquired on Huntington's disease was recently presented in Rome, Italy, during the annual conference of the Italian League for Research on Huntington's Foundation (In Italian: Fondazione Lega Italiana Ricerca Huntington or LIRH).
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If these new experimental neuroprotective strategies prove to be effective, patients may soon have additional therapies available compared to drugs that only act on certain symptoms, which is so far the only possible approach.
Huntington's Disease (HD) has about 6,500 patients and 40,000 people at risk of becoming ill in Italy. Although rare, it is the most frequent neurological dominant genetic disease with a known cause, detectable by genetic testing. Today there are three potential drugs under study, i.e. in the experimental phase, which aim to affect the mechanisms underlying the disease, and even to correct the genetic defect.
The parallels with what has already been observed in another rare disease, spinal muscular atrophy (SMA), are strong, and it is hoped that the results for HD will be equally positive. "The closest hope lies in the drug RG6042 that Roche is also experimenting in Italy in a large Phase III study - the GENERATION HD1 study", explains Prof. Ferdinando Squitieri, Head of the Huntington and Rare Diseases Research and Treatment Unit at the Research Hospital "Casa Sollievo della Sofferenza" and Scientific Director of the LIRH Foundation.
"It is an antisense oligonucleotide (ASO), i.e. a small fragment of synthetic DNA, able to recognize and bind to the messenger RNA to promote its degradation and thus reduce the levels of the huntingtin protein in the nervous system. The experimental therapy is administered periodically to patients with infiltration through an intrathecal lumbar puncture directly into the cerebral spinal fluid (CSF)" Prof. Squitieri explained. The type of drug and method of administration are the same as the first drug approved for Spinal Muscular Atrophy (SMA) Treatment, a therapy that amazed everyone with the speed with which it went from the experimental phase to approval.
"Even a second therapy under experimentation, which is in a slightly more preliminary phase of study, is represented by two different ASO drugs through a similar route of administration, but with a more selective action as it aims to reduce only the toxic huntingtin protein (the one produced by the mutated gene inherited from the sick parent): these molecules are produced by the pharmaceutical company Wave", added Prof. Squitieri.
The start of the Phase I/II trial is then expected in 2020 as the first possible gene therapy approach promoted by UniQure. "This therapy, whose molecule is called AMT-130 - explained Prof. Squitieri - exploits an adenoviral vector to convey a fragment of micro RNA (miRNA) that is integrated into the genome of the patient's brain cells by binding in a non-selective way to the messenger RNA that has the task of producing the huntingtin protein to promote its degradation, thus reducing its levels. After experimentation on a pig model, where it was seen that huntingtin levels (both healthy and mutated) were reduced by up to 70% and this result was maintained for up to a year after administration, it is now hoped to move on to the first phase of human experimentation. This therapy involves an injection directly into the brain through holes to be drilled in the skull by highly specialized personnel''.
(In Italian only) OMAR Osservatorio Malattie Rare. Malattia di Huntington, in 3 sperimentazioni la speranza di vincerla. 17 dicembre 2019